WO2020020210A1 - 免疫效应细胞治疗肿瘤的方法 - Google Patents
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- A61K2239/38—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterised by the dose, timing or administration schedule
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K39/46
- A61K2239/46—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterised by the cancer treated
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
- C07K2317/565—Complementarity determining region [CDR]
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
- C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
- C07K2317/622—Single chain antibody (scFv)
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
- C07K2319/03—Fusion polypeptide containing a localisation/targetting motif containing a transmembrane segment
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/33—Fusion polypeptide fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2510/00—Genetically modified cells
Definitions
- the invention belongs to the field of immunotherapy; in particular, it relates to immune cell therapy that targets and recognizes tumor antigens, triggers activation of immune effector cells, and exerts antitumor effects.
- MM Multiple myeloma
- the main condition is the infinite expansion and enrichment of plasma cells in the bone marrow, leading to osteonecrosis.
- the main treatment options are chemotherapy and stem cell transplantation.
- the chemotherapy drugs are mainly steroids, thalidomide, lenalidomide, bortezomib, and so on.
- BCMA B-cell maturation antigen
- B-cell mature antigen a type III transmembrane protein composed of 185 amino acid residues, belonging to the TNF receptor superfamily, and its ligand belongs to the TNF superfamily, such as the proliferation-inducing ligand (APRIL ), B lymphocyte stimulating factor (BAFF), BCMA can activate B cell proliferation and survival after binding to its ligand.
- APRIL proliferation-inducing ligand
- BAFF B lymphocyte stimulating factor
- BCMA can activate B cell proliferation and survival after binding to its ligand.
- BCMA is specifically overexpressed in plasma cells and multiple myeloma cells, but not in hematopoietic stem cells and other normal tissue cells. Therefore, BCMA can be an ideal target for targeted treatment of MM.
- An object of the present invention is to provide a technical means capable of having excellent killing effect on BCMA-positive tumors.
- a method for treating a BCMA-positive tumor comprising administering to a subject at least one course of an immune effector cell expressing a chimeric antigen receptor (CAR), the immune effector cell Specific recognition of BCMA.
- CAR chimeric antigen receptor
- the dose of immune effector cells per course of treatment does not exceed about 1 ⁇ 10 9 cells / kg of the subject's body weight or the total amount does not exceed about 1 ⁇ 10 10 .
- the dose of immune effector cells per course does not exceed about 1 ⁇ 10 8 cells / kg of the subject's body weight or the total amount of said cells does not exceed about 1 ⁇ 10 9 .
- the dose of immune effector cells per course does not exceed about 1 ⁇ 10 7 cells / kg of the subject's body weight or the total amount of said cells does not exceed about 5 ⁇ 10 8 .
- the total dose of immune effector cells in each course is not less than 1 ⁇ 10 5 .
- the total dose of immune effector cells in each course is not less than 1 ⁇ 10 6 .
- the total dose of immune effector cells in each course is not less than 1 ⁇ 10 7 .
- the subject is administered the immune effector cells for 2-5 courses.
- the immune effector cells are administered in a later course of treatment.
- the immune effector cells in the subsequent course are administered at a time point of about 4 to 24 weeks after the administration in the previous course.
- the dose of immune effector cells administered in a later course is lower than, equal to, or higher than the immune effector cells administered in a previous course.
- the dose of immune effector cells given in a later course is higher than the immune effector cells given in a previous course.
- the dose of the immune effector cells administered in the subsequent course is 2 times, 5 times, 7 times, or 10 times the dose of the previously administered immune effector cells.
- the immune effector cells of each course are divided into N administrations within 15 days, N is a natural number not less than 1, and in a preferred embodiment, N is 1, 2, 3, or 4.
- the subject when the immune effector cells are administered in a later course of treatment, the subject has any of the following characteristics:
- Factors indicative of cytokine release syndrome have a serum level fold in the subject that is about 10 times smaller and about 25 times smaller than the level in the subject immediately before the administration of immune effector cells in the previous course of treatment , And / or about 50 times smaller;
- neurotoxicity or CRS levels are reduced compared to peak levels of neurotoxicity or CRS levels after administration of immune effector cells during the previous course of treatment;
- the subject does not show a detectable humoral or cell-mediated immune response against CAR expressed by cells of the previous course of treatment.
- the CRS level is compared with the peak level of CRS after administration of immune effector cells in a previous course of treatment, The reduction is at least 50%, preferably, at least 20%, more preferably, at least 5%, or the CRS level is comparable to the CRS level prior to the administration of immune effector cells in the previous course of treatment.
- the method further comprises pre-treating the immune effector cells, the pre-treating comprising administering a chemotherapeutic agent or radiation therapy to the subject, or a combination thereof.
- said pretreatment is performed 2-12 days before the administration of immune effector cells. In a preferred embodiment, it is performed 2-7 days before the administration of immune effector cells.
- the chemotherapeutic agent is selected from any one or a combination of the following: cyclophosphamide, fludarabine.
- the fludarabine is administered an amount of about 10-50mg / m 2 / day, or about 15-40mg / m 2 / day, or about 15-35mg / m 2 / day, or 15 -30 mg / m 2 / day, or about 20-36 mg / m 2 / day, or about 20-30 mg / m 2 / day.
- the amount of fludarabine administered is about 20-30 mg / m 2 / day.
- the amount of fludarabine administered is about 20-26 mg / m 2 / day.
- the cyclophosphamide is administered is about 100-700mg / m 2 / day, or about 150-600mg / m 2 / day, or about 190-600mg / m 2 / day, or about 190 -560mg / m 2 / day.
- the cyclophosphamide is administered in an amount of about 150-400 mg / m 2 / day, preferably about 190-350 mg / m 2 / day.
- the administration of cyclophosphamide is about 400-600mg / m 2 / day, preferably about 450-600mg / m 2 / day, more preferably about 450-560mg / m 2 / day.
- fludarabine and cyclophosphamide are administered simultaneously, the respective doses of fludarabine and cyclophosphamide are also as described above.
- the chemotherapeutic agent is used continuously for no more than 6 days.
- the cyclophosphamide is used continuously for 1-5 days.
- the fludarabine is used continuously for 2-4 days.
- the tumor is multiple myeloma.
- the chimeric antigen receptor includes an antibody that specifically binds BCMA, a transmembrane domain, and an intracellular domain.
- the heavy chain and light chain variable regions of the antibody have:
- HCDR1 shown in SEQ ID NO: 1 HCDR2 shown in SEQ ID NO: 2, HCDR3 shown in SEQ ID NO: 3, and LCDR1 shown in SEQ ID NO: 6 and LCDR2 shown in SEQ ID NO: 7 LCDR3 shown in SEQ ID NO: 8; or
- HCDR1 shown in SEQ ID NO: 1 HCDR2 shown in SEQ ID NO: 2, HCDR3 shown in SEQ ID NO: 4, and LCDR1 shown in SEQ ID NO: 6 and LCDR2 shown in SEQ ID NO: 7 LCDR3 shown in SEQ ID NO: 9; or
- HCDR1 shown in SEQ ID NO: 1 HCDR2 shown in SEQ ID NO: 2
- HCDR3 shown in SEQ ID NO: 5 LCDR1 shown in SEQ ID NO: 6
- LCDR2 shown in SEQ ID NO: 7 LCDR3 shown in SEQ ID NO: 10; or
- HCDR1 shown in SEQ ID NO: 11 HCDR2 shown in SEQ ID NO: 12, HCDR3 shown in SEQ ID NO: 5, and LCDR1 shown in SEQ ID NO: 6, LCDR2 shown in SEQ ID NO: 7 LCDR3 shown in SEQ ID NO: 10; or
- HCDR1 shown in SEQ ID NO: 13 HCDR2 shown in SEQ ID NO: 14, HCDR3 shown in SEQ ID NO: 5, and LCDR1 shown in SEQ ID NO: 6 and LCDR2 shown in SEQ ID NO: 7 LCDR3 shown in SEQ ID NO: 10.
- the heavy chain variable region and light chain variable region of the antibody have HCDR1 shown in SEQ ID NO: 11, HCDR2 shown in SEQ ID NO: 12, and HCDR2 shown in SEQ ID NO: 12.
- the chimeric antigen receptor includes an antibody that specifically binds BCMA, a transmembrane domain, and an intracellular domain.
- the light chain variable region of the antibody has the sequence shown in SEQ ID NO: 6. LCDR1, LCDR2 shown in SEQ ID NO: 7, LCDR3 shown in SEQ ID NO: 10.
- the light chain variable region of the antibody has the amino acid sequence shown in SEQ ID NO: 20.
- the heavy chain variable region of the antibody has HCDR3 as shown in SEQ ID NO: 5.
- the heavy chain variable region of the antibody has the amino acid sequence shown in SEQ ID NO: 15 and the light chain variable region of the antibody has the amino acid sequence shown in SEQ ID NO: 16; or
- the heavy chain variable region of the antibody has the amino acid sequence shown in SEQ ID NO: 17 and the light chain variable region of the antibody has the amino acid sequence shown in SEQ ID NO: 18; or
- the heavy chain variable region of the antibody has the amino acid sequence shown in SEQ ID NO: 19 and the light chain variable region of the antibody has the amino acid sequence shown in SEQ ID NO: 20; or
- the heavy chain variable region of the antibody has the amino acid sequence shown in SEQ ID NO: 21 and the light chain variable region of the antibody has the amino acid sequence shown in SEQ ID NO: 20; or
- the heavy chain variable region of the antibody has the amino acid sequence shown in SEQ ID NO: 21 and the light chain variable region of the antibody has the amino acid sequence shown in SEQ ID NO: 20.
- the heavy chain variable region of the antibody has the amino acid sequence shown in SEQ ID NO: 21 and the light chain variable region of the antibody has the amino acid sequence shown in SEQ ID NO: 20.
- the antibody has the sequence of the scFv shown in SEQ ID NO: 25, 27, or 29.
- the chimeric antigen receptor has the amino acid sequence shown in SEQ ID NO: 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or 41.
- the chimeric antigen receptor has the amino acid sequence shown in any one of SEQ ID NO: 36, 37, and 38.
- the chimeric antigen receptor has an amino acid sequence represented by SEQ ID NO: 36.
- the immune effector cells are T cells, NK cells or NKT cells; in a preferred embodiment, the immune effector cells are T cells.
- the immune effector cell is from the subject's own body.
- said immune effector cell is from said allogeneic.
- the dosing interval of the immune effector cells is 4 to 24 weeks per course.
- the number of immune cells in each course of treatment is substantially the same.
- the number of immune effector cells administered in a later course is higher than the number of immune cells administered in a later course.
- the number of immune effector cells administered in a later course is lower than the number of immune cells administered in a later course.
- the subject prior to administering the immune effector cells, the subject has not been treated with immune cells that target a BCMA-expressing chimeric antigen receptor.
- the subject prior to administering the immune effector cell therapy, has undergone surgical treatment, chemotherapy, or immunotherapy different from a BCMA-targeting immune cell expressing a chimeric antigen receptor.
- the subject prior to administering immune effector cells for each course of treatment, the subject is indicated with a factor indicating CRS, a factor indicating neurotoxicity, a factor indicating tumor burden, and / or a host anti-CAR immunity
- a factor indicating CRS a factor indicating CRS
- a factor indicating neurotoxicity a factor indicating tumor burden
- a host anti-CAR immunity The serum levels of responding factors were evaluated.
- the factor indicating the tumor burden is: the total number of tumor cells in the subject, or the total number of tumor cells in the organ of the subject, or the tumor in the tissue of the subject The total number of cells, or the mass or volume of the tumor, or the degree of tumor metastasis, or the number of tumors.
- the factors indicating tumor burden include:
- the dose of the immune effector cells is about 0.1 ⁇ 10 6 cells / kg subject weight to 5 ⁇ 10 7 cells / kg subject weight, or the total dose of the immune effector cells is About 0.1x10 7 cells to 1x10 10 cells.
- the total dose of the immune effector cells is about 0.1 ⁇ 10 8 cells to 1 ⁇ 10 9 cells.
- the total dose of the immune effector cells is about 0.1 ⁇ 10 8 cells to 9 ⁇ 10 8 cells.
- the BCMA expression rate of the subject is greater than 50%, preferably, greater than 70%, or greater than 80%. More preferably, it is greater than 85%. More preferably, it is greater than 90%.
- the disease classification of the subject is IgG ⁇ type, or IgG ⁇ type, or IgA ⁇ type, or IgA ⁇ type, or ⁇ light chain type.
- Figure 1 shows the efficacy results for different groups of patients.
- Figure 2 shows the proliferation of BCMA CAR-T cells in a subject.
- CAR chimeric antigen receptor
- dose interval refers to the time elapsed between the administration of multiple courses of immune effector cell treatment to a subject and the administration of a pretreatment drug. Therefore, the dosing interval can be indicated as a range.
- the "dose” described herein may be expressed as a dose calculated on a weight basis or a dose calculated on a body surface area (BSA) basis.
- the dose calculated on the basis of the weight is the dose given to the patient calculated based on the weight of the patient, such as mg / kg, the number of immune effector cells / kg, and the like.
- the dose calculated based on BSA is the dose given to the patient based on the patient's surface area, such as mg / m2 and the number of immune effector cells / m2.
- number of administrations refers to the frequency with which a dose of immune effector cells or pretreatment drugs is administered within a given period of time.
- the number of dosing can be indicated as the number of doses per given time.
- fludarabine can be administered as follows: once daily for 4 consecutive days, once daily for 3 consecutive days, once daily for 2 consecutive days, or once daily.
- Cyclophosphamide can be administered as follows: once daily for 4 consecutive days, once daily for 3 consecutive days, once daily for 2 consecutive days, or once daily.
- This application relates to adoptive cells or immune effector cells for the treatment of tumors, including the administration of cells for one or more courses, and methods, compositions and articles of use thereof.
- Cells typically express a chimeric antigen receptor, for example, a chimeric antigen receptor (CAR) or other transgenic receptor such as a T cell receptor (TCR).
- CAR chimeric antigen receptor
- TCR T cell receptor
- the present invention provides methods and compositions for treating diseases (eg, tumors) associated with BCMA expression.
- the present invention provides a method for treating a tumor in a subject using adoptive cells or immune effector cells expressing a genetically engineered (recombinant) chimeric receptor.
- the method includes single-course infusion of adoptive cells or immune effector cells, or multi-course infusion.
- dose refers to the total number of adoptive cells or immune effector cells administered or returned within a course of treatment. In some embodiments, where multiple courses are included according to the methods described herein, the dose for each course is the same. In some embodiments, where a plurality of courses is included according to the methods described herein, the dose of each course is different.
- “Divided dose” refers to a single administration dose in the case where the dose of the entire treatment course is divided into multiple administrations to a subject within a course of treatment. In some embodiments, where the dose within a course of treatment is divided into multiple administrations to a subject, the divided dose for each administration is the same. In some embodiments, where the dose within a course of treatment is divided into multiple administrations to a subject, the divided dose for each administration is different. For the purposes of this document, doses refer to the total number of adoptive cells or immune effector cells administered or returned within a course of treatment, unless otherwise specified.
- the methods described herein include returning the adoptive cells or immune effector cells in a single course of treatment.
- a single course of treatment refers to returning a certain amount of adoptive cells or immune effector cells within a certain period of time.
- a certain amount of adoptive cells or immune effector cells are reinfused at one time during the course of treatment.
- a certain amount of adoptive cells or immune effector cells are infused back in two or more times.
- a certain amount of adoptive cells or immune effector cells are infused three or more times.
- each adoptive adoptive cell or immune effector cell is an aliquot of the adoptive cell or immune effector cell to be returned.
- each adoptive adoptive cell or immune effector cell is a non-equivalent portion of the adoptive cell or immune effector cell to be returned.
- the amount of adoptive cells or immune effector cells per infusion is determined by the physician based on the specific circumstances of the subject.
- the specific condition of the subject can be, for example, the overall health of the subject, the severity of the disease, the response to the previous dose of the same course of treatment, the response to the previous course of treatment, the combination of the subject, the degree of toxic reaction, or Likelihood, complications, and any other factors that the physician believes will affect the amount of adoptive or immune effector cells that the subject is suitable for infusion.
- the amount of adoptive cells or immune effector cells that are infused each time is increasing. In some embodiments, among the number of adoptive cells or immune effector cells that are infused a plurality of times, the amount of adoptive cells or immune effector cells that are infused each time decreases. In some embodiments, among the number of adoptive cells or immune effector cells that are infused a plurality of times, the number of adoptive cells or immune effector cells that are infused each time increases first and then decreases. In some embodiments, among the number of adoptive cells or immune effector cells that are infused back a plurality of times, the amount of adoptive cells or immune effector cells that are infused each time decreases first and then increases.
- Multi-course infusion refers to having a plurality of said time periods, and a certain amount of adoptive cells or immune effector cells are infused in each time period.
- the lengths of the plurality of time periods are uniform.
- the lengths of the plurality of time periods are unequal.
- the multiple courses refers to having at least two of the time periods. In some embodiments, the multiple courses refers to having at least three or more of the time periods.
- a certain amount of adoptive cells or immune effector cells are returned at a time within one of the plurality of treatment courses. In some embodiments, a certain amount of adoptive cells or immune effector cells are reinfused two or more times during one of the plurality of treatment courses. In some embodiments, a certain amount of adoptive cells or immune effector cells are returned in three or more times within one of the plurality of treatment courses. In some embodiments, within one of the multiple courses of treatment, the adoptive cells or immune effector cells returned each time are equal parts of the adoptive cells or immune effector cells to be returned.
- the adoptive cells or immune effector cells returned each time are non-equivalent parts of the adoptive cells or immune effector cells to be returned.
- the amount of adoptive cells or immune effector cells infused back within each course of the plurality of courses is determined by the physician according to the specific conditions of the subject.
- the specific condition of the subject can be, for example, the overall health of the subject, the severity of the disease, the response to the previous dose of the same course of treatment, the response to the previous course of treatment, the combination of the subject, the degree of toxic reaction Likelihood, complications, cancer metastasis, and any other factors that the physician believes will affect the amount of adoptive or immune effector cells that the subject is suitable for infusion.
- a certain amount of adoptive cells or immune effector cells are infused back in the same number of times in each of the plurality of treatment courses. In some embodiments, a certain amount of adoptive cells or immune effector cells are infused back at different times in each of the plurality of treatment courses. In some embodiments, a certain amount of adoptive cells or immune effector cells are infused back in the same number of times in each of the plurality of treatment courses. In some embodiments, the same amount of adoptive cells or immune effector cells are returned in each of the plurality of treatment courses. In some embodiments, a different amount of adoptive cells or immune effector cells are returned in each of the plurality of treatment courses.
- the total number of adoptive cells or immune effector cells in each of the plurality of treatment courses is increasing. In some embodiments, the total number of adoptive cells or immune effector cells in each of the plurality of treatment courses is decreasing. In some embodiments, the total number of the adoptive cells or immune effector cells in each of the plurality of treatment courses has a tendency of increasing first and then decreasing. The total amount of the adoptive cells or immune effector cells in each of the plurality of treatment courses has a tendency of decreasing first and then increasing.
- the methods described herein include monitoring a subject's degree of exposure to the adoptive cells or immune effector cells, and determining the dose and interval of subsequent divided doses or subsequent courses of treatment based on the degree of exposure time. In some embodiments, the methods described herein include monitoring a subject's degree of exposure to the adoptive cells or immune effector cells, and maintaining or reducing subsequent divided doses based on the degree of exposure reaching or exceeding a certain level or Dosing doses for subsequent courses and / or maintaining or extending the interval between subsequent divided doses or subsequent courses.
- the methods described herein include monitoring a subject's degree of exposure to the adoptive cells or immune effector cells, and maintaining or increasing subsequent fractional administration or follow-up based on the degree of exposure being below a certain level The administered dose of a course of treatment and / or maintaining or shortening the interval between subsequent divided doses or subsequent courses of treatment.
- the methods described herein include monitoring a subject's degree of toxicity or risk to the adoptive cells or immune effector cells, and determining subsequent fractional administration or subsequent treatment based on the degree of toxicity or risk The dose and interval of administration.
- the degree or risk of toxic reactions includes, but is not limited to, for example, CRS, neurotoxicity, macrophage activation syndrome, tumor lysis syndrome, and the like.
- immune effector cells are administered in a later course of treatment when a host-adaptive immune response to the cell has not been detected, has not been established, and / or has not reached a certain level or degree or stage.
- the so-called tumor burden includes typing, staging, the proportion of abnormal plasma cells in the bone marrow at the time of onset, cytogenetic changes, the presence of extramedullary infiltration, and the response to treatment.
- the tumor burden passes serum, Urine protein electrophoresis, bone marrow smear, bone marrow biopsy, MRD, MRI, and / or CT were evaluated.
- the immune effector cell is administered in an amount that includes a cell dose in an amount sufficient to reduce the tumor burden in the subject.
- the serum level of a factor indicative of cytokine-release syndrome (CRS) in a subject does not exceed 10 or 25 times the serum level of the subject prior to the administration of immune effector cells when cells are administered in a later course of treatment And / or the peak level of CRS-related results in the subject and began to decline after the administration of immune effector cells, and the subject did not have a chimeric antigen receptor specifically expressed by the cells of the immune effector cells in the previous course of treatment. Detection of adaptive host immune response.
- the immune effector cell is administered at a dose of not less than about 0.5 ⁇ 10 5 cells / kg of the subject's body weight or a total dose of not less than 1 ⁇ 10 5 cells; preferably, not less than about 0.1 ⁇ 10 6 cells / kg body weight or total dose is not less than 1x10 6 cells; preferably, not less than about 0.5x10 6 cells / kg subject weight or total dose is not less than 1x10 7 cells; preferably, not less than about 0.9x10 6 cells / kg body weight of the subject or the total dose of not less than 1x10 7 cells.
- the immune effector cells are administered at a dose of no more than about 1 ⁇ 10 9 cells / kg of the subject ’s weight or total amount not more than about 1 ⁇ 10 10 cells; preferably, no more than about 1 ⁇ 10 8 cells or the total number of cells
- the amount does not exceed about 1x10 9 cells; preferably, not more than about 1x10 7 cells or the total number of cells does not exceed about 1x10 9 cells, preferably, not more than about 5x10 6 cells or the total number of cells does not exceed about 9x10 8 cell.
- the dose of the immune effector cells is about 0.1 ⁇ 10 6 cells / kg subject weight to 5 ⁇ 10 7 cells / kg subject weight, or the total dose of the immune effector cells is About 0.1x10 7 cells to 1x10 10 cells.
- it is about 0.5 ⁇ 10 6 cells / kg subject weight to 1 ⁇ 10 7 cells / kg subject weight, or the total dose of the immune effector cells is about 0.1 ⁇ 10 8 cells to 1 ⁇ 10 9 cells. More preferably, it is about 0.9 ⁇ 10 6 cells / kg subject weight to 5 ⁇ 10 6 cells / kg subject weight, or the total dose of the immune effector cells is about 0.1 ⁇ 10 8 cells to 9 ⁇ 10 8 cells.
- the method provided by the present invention comprises administering at least one course of immune effector cells expressing a chimeric antigen receptor (such as CAR, TCR, TFP, TAC) that recognizes BCMA to a tumor subject expressing BCMA.
- a chimeric antigen receptor such as CAR, TCR, TFP, TAC
- a "subject" is a mammal, such as a human or other animal, usually a human.
- the subject has been treated with chemotherapy or radiation prior to the administration of immune effector cells in a previous course and / or the administration of immune effector cells in a subsequent course.
- the subject is refractory or non-responsive to other therapeutic agents.
- the tumor is persistent or relapsed, for example, after intervention with another treatment (including chemotherapy, radiation), the tumor still progresses or relapses after control. .
- the subject is responsive to other therapeutic agents, reducing tumor burden.
- the subject is initially responsive to the therapeutic agent, but shows recurrence of the tumor over time.
- the subject is determined to have a risk of recurrence, for example at a high risk of recurrence, and thus the CAR T cells of the invention are prophylactically administered in order to reduce the likelihood of recurrence or prevent recurrence.
- the size of the dose and the time of infusion are determined by the subject's initial tumor burden. For example, in some cases, the number of cells of immune effector cells that are generally given to the subject during the previous course of treatment is lower, and in the case of lower tumor burden, such as solid tumors, tumor tumor size can be assessed by tumor marker detection and / Or small residual lesions, the initial dose may be higher. In other cases, in subjects with higher tumor burden, continuous cell infusions can be used for each course, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10
- the single administration is preferably 1-5 administrations, and more preferably, 2-3 administrations. Each administration is separated by 1, 2, 3, 4, 5, 6 days or more.
- treatment refers to the complete or partial reduction or reduction of a tumor or a symptom associated therewith, and the improvement of an objective indicator related to the assessment. Desired therapeutic effects include, but are not limited to, preventing the occurrence or recurrence of a tumor, reducing symptoms, reducing any direct or indirect pathological results of the tumor, preventing extramedullary disease, slowing the rate of tumor progression, improving or reducing the state of the tumor, and reducing or Improve prognosis.
- inhibiting a function or activity means a reduction in function or activity when compared to the same condition in other circumstances or compared to another condition.
- the cell therapy can be treated by autologous infusion.
- the cells are derived from a subject in need of treatment and are administered to the same subject after isolation and processing.
- the cell therapy is treated by allogeneic infusion, wherein the cells are isolated and / or otherwise extracted and prepared from the donor, and the donor and the subject returning the cells different.
- the donor and recipient are genetically the same.
- the donor and recipient are genetically similar.
- the recipient and the donor are of the same HLA category or supertype.
- the cells can be administered by any suitable means, for example, by injection, such as intravenous injection, intraocular injection, fundus injection, subretinal injection, intravitreal injection, reverse interval injection, subscleral injection, intrachoroidal injection, anterior chamber Injection, subconjectval injection, subconjuntival injection, suprascleral injection, post-ball injection, periocular injection, or peri-ball delivery.
- injection such as intravenous injection, intraocular injection, fundus injection, subretinal injection, intravitreal injection, reverse interval injection, subscleral injection, intrachoroidal injection, anterior chamber Injection, subconjectval injection, subconjuntival injection, suprascleral injection, post-ball injection, periocular injection, or peri-ball delivery.
- the cells are administered by drip.
- the cells are administered by multiple instillations, for example, multiple administrations over no more than 30 days, or the cells are administered by continuous infusion.
- the dose administered may depend on the type of disease, the chimeric antigen receptor or cell type, the severity and duration of the disease, the subject's previous treatment history, and the response of the administered cells, and the treating physician Judge's judgment.
- the immune effector cells are used as part of a combination therapy, for example, in combination with another interventional therapy, such as antibodies, engineered immune effector cells, receptors or agents, cytotoxic drugs, or other treatment methods , Given simultaneously or sequentially, in any order.
- immune effector cells are used in combination with one or more other treatments, or in combination with another interventional treatment, simultaneously or sequentially in any order.
- the immune effector cells are co-administered with another treatment at a time close enough to produce a therapeutic effect greater than the aforementioned immune effector cell population or one or more other therapeutic drugs or methods, and vice versa.
- the immune effector cell is administered before one or more other therapeutic agents.
- the immune effector cell is administered after one or more other therapeutic agents.
- one or more other therapeutic agents include cytokines, such as IL-2, IL-12, to enhance persistence.
- the method includes administering a pretreatment prior to administering immune effector cells, such as, for example, a chemotherapeutic drug (chemotherapeutic agent), systemic radiation, local radiation therapy, etc., or a combination thereof.
- a chemotherapeutic drug chemotherapeutic agent
- the method includes pretreating the subject with one or more chemotherapeutic agents.
- the method comprises pretreating a subject with a tubulin inhibitor and one or more other chemotherapeutic agents.
- the effects of pretreatment are considered to include, but not limited to, lymphocyte clearance, reducing tumor burden, and the like.
- the chemotherapeutic agent refers to a drug used in chemotherapy, for example, cyclophosphamide, fludarabine, a protease inhibitor (such as bortezomib, carfilzomib, etc.), an immunomodulator (such as thalidomide, Lenalidomide, pomalidomide, etc.), melphalan, doxorubicin, dexamethasone, prednisone, etc.
- a drug used in chemotherapy for example, cyclophosphamide, fludarabine, a protease inhibitor (such as bortezomib, carfilzomib, etc.), an immunomodulator (such as thalidomide, Lenalidomide, pomalidomide, etc.), melphalan, doxorubicin, dexamethasone, prednisone, etc.
- Pretreatment can improve the effect of immune effector cell therapy.
- the first day of infusion of immune effector cells e.g., CAR T cells
- Pretreatment can be given at any time prior to the administration of immune effector cells.
- fludarabine or cyclophosphamide is used alone or in combination as a pretreatment, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 9 before CAR-T cell infusion. 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 days, preferably at least 1, 2 , 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 days, more preferably, at least 2, 3, 4, 5 Subjects were administered on, 6, 7, or 8 days.
- pretreatment includes administering fludarabine and cyclophosphamide 2-12 days before CAR-T cell infusion. In some embodiments, pretreatment includes administering fludarabine and cyclophosphamide 7 days before CAR-T cell infusion.
- the timing of the pretreatment component can be adjusted so that the CAR T treatment achieves the maximum effect.
- fludarabine and cyclophosphamide can be given daily.
- fludarabine is administered daily
- cyclophosphamide is administered for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days.
- fludarabine is administered daily for 4 consecutive days
- cyclophosphamide is administered daily for 2 consecutive days.
- fludarabine is administered daily for 2 consecutive days
- cyclophosphamide is administered daily for 2 consecutive days.
- fludarabine is administered daily for 3 consecutive days
- cyclophosphamide is administered once, or cyclophosphamide is administered continuously for 2 or 3 or 5 days.
- the day when the patients were given CAR T cell therapy in each round was designated as the 0th day.
- the patient is given fludarabine on the 6th (i.e., -6th), -5th, and -4th days before the 0th day.
- the patient is administered fludarabine on days -5, -4, and -3.
- the patient is administered fludarabine on days -6, -5, -4, and -3.
- the patient is administered fludarabine on days -5, -4, -3, and -2.
- the patient is administered fludarabine on days -4, -3, and -2.
- the patient is administered fludarabine on days -3 and -2. In some embodiments, the patient is administered fludarabine on days -3, -2, and -1. In some embodiments, the patient is administered cyclophosphamide on days -6, -5, -4, -3, and -2. In some embodiments, the patient is administered cyclophosphamide on days -6 and -5. In some embodiments, the patient is administered cyclophosphamide on days -4, -3, and -2. In some embodiments, the patient is administered cyclophosphamide on days -4 and -3. In some embodiments, the patient is administered cyclophosphamide on days -5 and -4.
- the patient is administered cyclophosphamide on day -5. In some embodiments, the patient is administered cyclophosphamide on days -3 and -2. In some embodiments, the patient is administered cyclophosphamide on days -3, -2, and -1.
- Fludarabine and cyclophosphamide can be given on the same day or on different days.
- fludarabine and cyclophosphamide may be administered simultaneously or sequentially.
- Fludarabine and cyclophosphamide can be administered by any route, including intravenous drip (I.V.). In some embodiments, fludarabine and cyclophosphamide can be administered according to the drug instructions for fludarabine and cyclophosphamide.
- I.V. intravenous drip
- fludarabine and cyclophosphamide can be administered according to the drug instructions for fludarabine and cyclophosphamide.
- adoptive cell therapy or immune effector cell therapy is selected from the group consisting of tumor infiltrating lymphocyte (TIL) immunotherapy, autologous cell therapy, engineered autologous cell therapy (eACT), and allogeneic T cell transplantation.
- TIL tumor infiltrating lymphocyte
- eACT engineered autologous cell therapy
- allogeneic T cell transplantation is selected from the group consisting of tumor infiltrating lymphocyte (TIL) immunotherapy, autologous cell therapy, engineered autologous cell therapy (eACT), and allogeneic T cell transplantation.
- the immune effector cell therapy is the administration of a chimeric antigen receptor modified T cell that targets a tumor antigen (such as BCMA).
- pretreatment includes administering fludarabine no higher than about 50, 49, 48, 47, 46, 45, 44, 43, 42, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1 mg / m 2 / day; and / or given cyclophosphamide not higher than about 700, 690, 680, 670, 660, 650, 640, 630, 620, 610, 600, 595, 590, 585, 580, 579, 578, 576, 575, 574, 573, 572, 571, 570, 569, 568, 567, 566, 565, 564, 563, 562, 561, 560, 559, 558, 557, 556, 555, 554, 553, 552, 551, 550, 549, 548, 547, 546, 545,
- the fludarabine is administered an amount of about 10-50mg / m 2 / day, or about 15-40mg / m 2 / day, or about 15-35mg / m 2 / day, 15-30mg or / m 2 / day, or about 20-30 mg / m 2 / day.
- the cyclophosphamide is administered is about 100-700mg / m 2 / day, or about 150-600mg / m 2 / day,, or from about 190-600mg / m 2 / day, or about 190 to 560 mg / m 2 / day.
- the cyclophosphamide is administered in an amount of about 150-400 mg / m 2 / day, preferably about 190-350 mg / m 2 / day.
- the cyclophosphamide is administered is about 400-600mg / m 2 / day, preferably about 450-600mg / m 2 / day, more preferably about 450-560mg / m 2 / day.
- cyclophosphamide and fludarabine may cause adverse reactions in patients after administration.
- the scope of the invention includes administering a composition to a patient to reduce some of these adverse events.
- the method comprises administering physiological saline to the patient.
- the patient may be given saline before or after administration of cyclophosphamide and / or fludarabine, or before and after administration of cyclophosphamide and / or fludarabine.
- the patient is given saline before cyclophosphamide and / or fludarabine is administered on each infusion day, and after cyclophosphamide and / or fludarabine is administered.
- adjuvants and excipients can be administered to patients.
- mesna sodium 2-mercaptoethanesulfonate
- patients can be administered exogenous cytokines.
- pretreatment prior to infusion of immune effector cells in a previous course or immune effector cells in a subsequent course improves the outcome of the treatment. For example, in some aspects, pretreatment improves the efficacy of treatment with immune effector cells in a previous course or immune effector cells in a later course, or increases the persistence of immune effector cells (such as CAR-T cells) in a subject . In some embodiments, pretreatment treatment increases the stable phase of the disease.
- the sustained survival of the immune effector cell population in vivo and its biological activity are measured by any of a number of known methods.
- the continuous survival period of CAR-T cells in vivo is the continuous survival period of CAR-T cells in vivo after the "implantation" of CAR-T cells.
- the number of copies of CAR DNA contained in peripheral blood was detected by Q-PCR at the visiting points until any two consecutive tests were negative, and the CAR-T cell survival period was recorded.
- the biological activity of immune effector cells can be assessed by the specific binding of engineered or natural T cells or other immune cells to the antigen, such as by ELISA or flow cytometry.
- the cell killing capacity of engineered immune effector cells can be detected using any suitable method known in the art, such as by measuring certain cytokines such as CD107a, IFN ⁇ , IL-2 and TNF Expression and / or secretion to measure the biological activity of immune effector cells.
- biological activity is assessed by clinical outcomes, such as tumor burden or reduction in burden.
- the cells are evaluated for toxicity, persistence and / or proliferation, and / or the presence or absence of a host immune response.
- the administration of a given "dose” includes a single composition and / or a single uninterrupted administration, such as a single injection or continuous infusion to a given amount or number of immune effector cells, and Also included in no more than 30, 29, 28, 27, 26, 25, 24, 23, 22, 20, 19, 18, 17, 16, 15, 15, 14, 13, 12, 11, 10, 9, 8, 7
- a given period of time of 6, 6, 5, 4, 3 or 2 days divided doses are provided in multiple separate compositions or infusions to give a given amount or number of immune effector cells. Therefore, each course of immune effector cells is a single or continuous administration of a specified number of immune effector cells given or started at a single time point.
- the immune effector cells in each course do not exceed 30, 29, 28, 27, 26, 25, 24, 23, 22, 20, 19, 18, 17, 16, 15, 14, 14, 13 Multiple injections or infusions over a period of 1, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, or 2 days, such as once a day for three or two days, or by one day Multiple infusions within.
- the immune effector cells of the previous course of immune effector cells are administered as a single pharmaceutical composition.
- the term "after the course of treatment” refers to the dose given to the subject without any intervening doses being given to the subject during the period after the first course of treatment. Nonetheless, the term does not include the second, third, and / or other injections or infusions in a series of infusions or injections contained in a single divided dose. Therefore, unless otherwise stated, a second infusion within one, two, or three days is not considered a "post-treatment course” as used herein. Similarly, the second, third, and other doses in a series of multiple doses within a divided dose are not considered to be “intervening" doses in the meaning of the "after course” dose.
- the dose given over a period of more than 30 days after the first course or after the start of the first course The dose considered to be "after the course".
- multiple administrations of the same immune effector cells are considered as a single dose over a period of up to 30 days, and 30 days after the initial administration (the first infusion of each course (i.e. the initial Administration of immune effector cells on the first day of the day) is not considered to be administered after the course of treatment and is not considered to determine whether the second dose is "continuous" with the immune effector cells of the previous course of treatment. Insert dose.
- first course is used to describe the total dose administered during the first course of treatment performed according to the methods described herein. This dose is equal to the total dose given in a single course of administration, or the total dose given in the first course of multiple courses.
- the term does not necessarily mean that the subject has never been treated with immune effector cells before, or that the subject has not previously been treated with immune effector cells that target the same antigen.
- the size of the dose of the immune effector cells of the previous course and / or of the immune effector cells of the subsequent course is usually designed to provide improved efficacy and / or reduced risk of toxicity.
- the immune cell dose per course is higher than, lower than, or equal to about 0.5 ⁇ 10 6 cells / kg subject weight to 1 ⁇ 10 7 cells / kg subject weight, such as higher, lower, or Equal to about 0.6 ⁇ 10 6 , 0.7 ⁇ 10 6 , 0.8 ⁇ 10 6 , 0.9 ⁇ 10 6 , 1.0 ⁇ 10 6 , 1.1 ⁇ 10 6 , 1.2 ⁇ 10 6 , 1.3 ⁇ 10 6 , 1.4 ⁇ 10 6 , 1.5 ⁇ 10 6 , 1.6 ⁇ 10 6 , 1.7 ⁇ 10 6 , 1.8 ⁇ 10 6 , 1.9 ⁇ 10 6 , 2.0 ⁇ 10 6 , 2.1 ⁇ 10 6 , 2.2 ⁇ 10 6 , 2.3 ⁇ 10 6 , 2.4 ⁇ 10 6 ,
- the total dose of immune cells administered per course is higher than, lower than, or equal to about 0.1 ⁇ 10 8 cells to 1 ⁇ 10 10 cells.
- it is higher than, lower than or equal to about 1 ⁇ 10 6 cells / kg subject weight to 1 ⁇ 10 7 cells / kg subject weight, or the total dose of the immune effector cells is higher, lower or Equal to about 0.5x10 8 cells to 1x10 9 cells.
- it is higher than, lower than or equal to about 1.5x10 6 cells / kg subject weight to 3x10 6 cells / kg subject weight, or the total dose of the immune effector cells is about 0.5x10 8 cells to 5x10 8 cells.
- the number of immune effector cells refers to the number of immune effector cells expressing the chimeric antigen receptor, such as the number of CAR-T cells. In other embodiments, the number of immune effector cells may also refer to the number of T cells or PBMCs or total cells administered.
- the dose after the course of treatment is sufficient to reduce tumor burden or an indicator thereof, and / or one or more symptoms of the disease or disorder.
- the tumor burden such as the proportion of plasma cells in the bone marrow, blood / urinary M protein, and extramedullary soft tissue plasma cell tumors, is reduced by about 1 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 100%.
- M protein is a large number of abnormal immunoglobulins produced by the malignant proliferation of plasma cells or B lymphocytes.
- the dose specifically disclosed in the present invention is a safe and effective dose obtained by the inventor after research.
- Those skilled in the art may The tumor load, the patient's own physical condition, and other factors determine the dose of immune effector cells in the previous course of treatment; if further administration of immune effector cells in the later course of treatment is needed, those skilled in the art can, for example, change the tumor load after giving immune effector cells To determine the dose of immune effector cells in the later course of treatment.
- the dose of immune effector cells for each course includes an amount that does not cause or reduce toxicity, and the toxicity may be cytokine release syndrome (CRS), severe CRS (sCRS), macrophage activation Syndrome, tumor lysis syndrome, fever of at least 38 degrees Celsius or about 38 degrees Celsius for three or more days, CRP plasma levels at least equal to about 20 mg / dL, and / or neurotoxicity.
- the number of cells administered in an immune effector cell after a course of treatment is determined based on the likelihood that the subject will show toxicity or toxic results after the cells are administered. For example, in some embodiments, the likelihood of developing a toxic outcome in a subject is predicted based on tumor burden.
- the method includes detecting or assessing toxicological results and / or tumor burden before administering immune effector cells.
- the dosing time in the subsequent course is calculated from the completion of the previous course (the total dose infusion completion date of the previous course is set to 0 day).
- the serum level of a factor indicative of CRS in a subject is no more than about 10-fold, 25-fold, 50-fold, or 50-fold greater than the serum level of the indicator in the subject after the administration of immune effector cells in the previous course At 100 times, immune effector cells were administered during the subsequent course.
- a CRS-related result e.g., a serum factor associated with or indicative of CRS
- a clinical sign or symptom such as fever, hypoxia, hypotension, or neurological disorder in a subject
- the immune effector cells are given in the later course of treatment.
- the immune effector cells are administered during a later course of treatment when a decrease is observed after administration compared to the highest level of such results, or when the maximum or level of results is reached after administration.
- an indicator of a toxic effect eg, a serum indicator of CRS
- the Immune effector cells are administered after a course of treatment when the subject does not show CRS or does not show severe CRS.
- the immune effector cells in the subsequent course are administered at a time point when the tumor load in the patient is reduced compared to the tumor load before the immune effector cells administered in the previous course.
- the immune effector cells of the subsequent course of treatment are given the immune effector cells of the previous course of treatment, when the tumor burden such as the proportion of plasma cells in the bone marrow, blood / urine M protein, extramedullary soft tissue plasmacytoma has been reduced 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or more.
- the immune effector cell in a subsequent course is administered when the subject's disease or condition does not recur after a decrease in response to the previous course or in response to the previous dose.
- reducing tumor burden is indicated by a reduction in one or more indicators, such as typing, staging, the proportion of abnormal plasma cells in the bone marrow at the time of onset, cytogenetic changes, the presence of extramedullary infiltration, and Response after treatment.
- immune effector cells are administered in a later course of treatment when the host adaptive immune response has not been detected, has not been established, or has not reached a certain level, degree, or stage. In some aspects, immune effector cells are administered in a later course of treatment before the subject's memory immune response develops.
- the time between the administration of immune effector cells in a previous course and the administration of immune effector cells in a subsequent course is from about 4 weeks to about 24 weeks.
- additional or further immune effector cells are administered after the subsequent course of immune effector cells, for example, a second immune effector cell (the third course dose), a third Immune effector cells in the later course (dose of the fourth course), and so on.
- the tumor burden is reduced by at least about 25%, 30%, after administration of the immune effector cells in the subsequent course, compared to the time immediately before or after the immune effector cells in the subsequent course, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or more.
- tumor burden can be assessed by serum, urine protein electrophoresis, bone marrow smear, bone marrow biopsy, MRD, MRI, and / or CT.
- one or more doses does not exist in the subject's immune response (eg, an adaptive or specific immune response to a transgenic receptor or cell), and is not detectable, Or when it can not be detected above a certain level.
- the presence or extent of a specific immune response to a transgene is often related to the immunogenicity of the recipient (e.g., a CAR expressed by a cell or a transgenic TCR) and / or the time the subject is exposed to the cell.
- an immune response, an adaptive or specific immune response, a detectable immune response, and / or a memory response to a chimeric antigen receptor or cell has been developed in a subject. Effector cells.
- the decision of when and / or whether to give immune effector cells at a later course of treatment depends on whether the subject exhibits such an immune response or a detectable reading thereof, such as for a cell or a chimeric antigen receptor Specific detectable specific or adaptive host immune responses, such as CAR expressed by cells of immune effector cells in a previous course of treatment, and / or whether such a response was detected at a certain level.
- the subject is not administered an immune effector cell at a later course of treatment.
- a specific or adaptive (e.g., humoral or cell-mediated) immune response to the receptor e.g., CAR expressed by cells of an immune effector cell in the previous course
- a detectable level or an acceptable level of such a response or indicator is administered to immune effector cells during a later course of treatment.
- the subject exhibits reduced humoral or cell-mediated CAR against cells expressed by immune effector cells of the previous course of treatment when administered to immune effector cells of the later course of treatment compared to when the initial dose is greater. Immune response.
- provided methods increase the persistence of a subject to an administered immune effector cell, e.g., an increase in the number or duration of cells over time, and / or improve efficacy and treatment outcomes in immune cell therapy .
- this method has the advantage that compared to other methods, cells (such as CAR-T cells) that express the chimeric antigen receptor can improve treatment outcomes to a greater extent and / or longer. These results can include patient survival and remission, even in subjects with severe tumor burden.
- the presence of cells expressing a chimeric antigen receptor e.g., CAR-expressing cells
- a chimeric antigen receptor e.g., CAR-expressing cells
- quantitative PCR is used to assess the amount of cells (e.g., CAR-T) that express a chimeric antigen receptor in the subject's blood or serum or organ or tissue (e.g., a disease site).
- persistence is quantified as a copy of DNA or plasmid encoding a receptor per microgram of DNA, such as CAR, or as receptor expression per microliter of sample, such as blood or serum, such as the number of CAR-expressing cells, or Total number of peripheral blood mononuclear cells (PBMC) or white blood cells or T cells per microliter of sample.
- a receptor per microgram of DNA such as CAR
- receptor expression per microliter of sample such as blood or serum, such as the number of CAR-expressing cells, or Total number of peripheral blood mononuclear cells (PBMC) or white blood cells or T cells per microliter of sample.
- PBMC peripheral blood mononuclear cells
- the administration of immune effector cells in a previous course or at least on the 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 15, Cells were detected in the subject at 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 days.
- at least at least 2, 4, or 6 weeks after the first or subsequent course of immune effector cells are administered, or at 3, 6 or 12, 18 or 24, or 30 or 36 months, or 1, 2, 3 Cells were detected at 4, 4, 5 or more years.
- the method results in at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 500, 1000, Maximum concentration of 1500, 2000, 5000, 10,000, or 15,000 copies or receptor-encoding nucleic acids, such as CAR per microgram of DNA, or at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, or 0.9 Somatic expression, such as the total number of CAR-expressed cells / peripheral blood mononuclear cells (PBMC), total monocytes, total T cells, or total microliters.
- PBMC peripheral blood mononuclear cells
- the receptor-expressing cells are detected as at least 10%, 20%, 30%, 40%, 50%, or 60% of the total PBMCs in the subject's blood, and / or at this level upon first administration Drug or subsequent administration for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 24, 36, 48, or 52 weeks, or for 1 week after such administration , 2, 3, 4 or 5 years or more.
- the method results in, for example, a copy of a nucleic acid encoding a chimeric antigen receptor, such as CAR, in a subject's serum increased by at least 2-fold, at least 4-fold, at least 10-fold, or at least 20-fold per microgram of DNA.
- a chimeric antigen receptor such as CAR
- the receptor-expressing cells can be detected in the subject's blood or serum, for example, by a specified method, such as qPCR or a flow cytometry-based detection method, the immune effector cells given to the previous course of treatment At least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 16, 17, 18, 19 after administration of immune effector cells , 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 44 , 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 or 60 or more days, or after the administration of immune effector cells in a previous course or later
- the course of immune effector cells continues for at least or about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 or more weeks.
- the number of copies of a nucleic acid encoding a chimeric antigen receptor per 100 cells such as a vector copy number, such as in peripheral blood or bone marrow or In the chamber, at least 0.01, at least 0.1, at least 1, or at least 10, the cells are administered, for example, about 1 week, about 2 weeks, about 3 weeks after the immune effector cells in the previous course or the immune effector cells in the subsequent course Week, about 4 weeks, about 5 weeks, or at least about 6 weeks, or at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or at least 2 or 3 years .
- the immune effector cells express a chimeric antigen receptor that recognizes BCMA or a variant thereof.
- the chimeric antigen receptor (CAR) usually includes an extracellular antigen-binding domain, such as a part of an antibody molecule, which is usually a variable antibody. Heavy (VH) chain regions and / or variable light (VL) chain regions, such as scFv antibody fragments.
- the heavy chain and light chain variable regions of the antibody have: HCDR1 shown in SEQ ID NO: 1, HCDR2 shown in SEQ ID NO: 2, and HCDR2 shown in SEQ IDNO: 2 HCDR3, and LCDR1 shown in SEQ ID NO: 6, LCDR2 shown in SEQ ID NO: 7, LCDR3 shown in SEQ ID NO: 8, or at least 85%, 86%, 87%, 88 %, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical amino acid sequences; or HCDR1 shown in SEQ ID NO: 1 , HCDR3 shown in SEQ ID NO: 2, HCDR3 shown in SEQ ID NO: 4, and LCDR1 shown in SEQ IDNO: 6, LCDR2 shown in SEQ IDNO: 7, LCDR2 shown in SEQ IDNO: 7, and LCDR3, or at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%
- the heavy chain variable region and light chain variable region of the antibody have HCDR1 shown in SEQ ID NO: 11, HCDR2 shown in SEQ ID NO: 12, and SEQ ID NO: 5 HCDR3 and LCDR1 shown in SEQ ID NO: 6, LCDR2 shown in SEQ ID NO: 7, LCDR3 shown in SEQ ID NO: 10, or at least 85%, 86%, 87%, 88% of the above sequence , 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity amino acid sequences.
- the light chain variable region of the antibody has LCDR1 shown in SEQ ID NO: 6, LCDR2 shown in SEQ ID NO: 7, LCDR3 shown in SEQ ID NO: 10, or the same sequence as above Amino acids with at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity sequence.
- the light chain variable region of the antibody has the amino acid sequence shown in SEQ ID NO: 20, or has at least 85%, 86%, 87%, 88%, 89%, 90% of the above sequence. , 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity amino acid sequences.
- variable region of the heavy chain of the antibody has HCDR3 shown in SEQ ID NO: 5
- variable region of the light chain has the amino acid sequence shown in SEQ ID NO: 20, or has at least 85 with the above sequence. %, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity amino acid sequences.
- the heavy chain variable region of the antibody has the amino acid sequence shown in SEQ ID NO: 15 and the light chain variable region of the antibody has the amino acid sequence shown in SEQ ID NO: 16, or Identical to the above sequence with at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%
- the variable region of the heavy chain of the antibody has the amino acid sequence shown in SEQ ID NO: 17 and the variable region of the light chain of the antibody has the amino acid sequence shown in SEQ ID NO: 18, or Identical to the above sequence with at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%
- the light chain variable region of the antibody has the amino acid sequence shown in SEQ ID NO: 19 and the light chain variable region of the antibody has the amino acid sequence shown in SEQ ID NO: 20, or With at least 85%, 8
- the heavy chain variable region of the antibody has the amino acid sequence shown in SEQ ID NO: 21 and the light chain variable region of the antibody has the amino acid sequence shown in SEQ ID NO: 20, or Identical to the above sequence with at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% Sexual amino acid sequence.
- the antibody has the sequence of the scFv shown in SEQ ID NO: 25, 27, or 29, or has at least 85%, 86%, 87%, 88%, 89%, 90% of the sequence described above. , 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity amino acid sequences.
- the chimeric antigen receptor has the amino acid sequence shown in SEQ ID NO: 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or 41, or The above sequence has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity Amino acid sequence.
- the chimeric antigen receptor has the amino acid sequence shown in any one of SEQ ID NO: 36, 37, 38, or has at least 85%, 86%, 87%, 88%, Amino acid sequences with 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity.
- the chimeric antigen receptor has the amino acid sequence shown in SEQ ID NO: 36, or has at least 85%, 86%, 87%, 88%, 89%, 90%, Amino acid sequences with 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity.
- the antibody portion of a chimeric antigen receptor further includes a linker sequence, which may be or include at least a portion of an immunoglobulin constant region or a variant or modified form thereof, such as a hinge region, such as IgG4 hinge region and / or CH1 / CL and / or Fc region.
- a linker sequence which may be or include at least a portion of an immunoglobulin constant region or a variant or modified form thereof, such as a hinge region, such as IgG4 hinge region and / or CH1 / CL and / or Fc region.
- the constant region or portion is of human IgG, such as IgG4 or IgG1.
- the antigen recognition domain is typically linked to one or more intracellular signal transduction moieties, such as in the case of CAR, mimicking an activated signal transduction moiety through an antigen receptor complex (eg, a TCR complex), and / or via Signal from another cell surface receptor.
- an antigen-binding component eg, an antibody
- the transmembrane domain is fused to the extracellular domain.
- a transmembrane domain that is one of the domains in a naturally associated receptor (eg, CAR) is used.
- the transmembrane domain is selected or modified by amino acid substitution to avoid binding the domain to the transmembrane domain of the same or different surface membrane protein, so that Minimize interaction.
- the transmembrane domain is derived from a natural or synthetic source.
- the domain is derived from any membrane-bound or transmembrane protein.
- Transmembrane regions include ⁇ -, ⁇ -, or ⁇ chains derived from T-cell receptors, CD28, CD3 ⁇ , CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134 CD137, CD154, and / or transmembrane regions contain those functional variants (such as those that substantially retain their structural parts (eg, transmembrane structural parts), properties) (ie, include at least their transmembrane regions).
- the transmembrane domain is a transmembrane domain derived from CD4, CD28, or CD8, such as CD8 ⁇ or a functional variant thereof.
- the transmembrane domain is synthetic.
- the synthetic transmembrane domain mainly comprises hydrophobic residues such as leucine and valine.
- trimers of phenylalanine, tryptophan, and valine will occur at each end of a synthetic transmembrane domain.
- the linking occurs through a linker, a spacer, and / or a transmembrane domain.
- the intracellular signal transduction domain includes those that mimic or approximate signals through natural antigen receptors, signals that co-stimulate receptors through such receptors, and / or signals that co-stimulate receptors alone.
- a short oligopeptide or polypeptide linker is present, for example, a linker that is 2-10 amino acids in length, such as a linker comprising glycine and serine, for example, a glycine-serine duplex, and in the cytoplasm of the CAR A connection is formed between the signal transduction domain and the transmembrane domain.
- the receptor for example, CAR, generally includes at least one type of one or more intracellular signal transduction moieties.
- the receptor includes an intracellular component of a TCR complex, such as a TCRCD3 + chain, such as a CD3 ⁇ chain, that mediates T-cell activation and cytotoxicity.
- the antigen binding moiety is connected to one or more cellular signal transduction modules.
- the cell signal transduction module includes a CD3 transmembrane domain, a CD3 intracellular signal transduction domain, and / or other CD transmembrane domains.
- the receptor eg, CAR
- the receptor further comprises a portion of one or more other molecules, such as an Fc receptor gamma, CD8, CD4, CD25, or CD16.
- a CAR or other chimeric antigen receptor includes a chimeric molecule between CD3 [zeta] (CD3- [zeta]) or an Fc receptor [gamma] and CD8, CD4, CD25, or CD16.
- the cytoplasmic domain or intracellular signal transduction domain of the receptor activates at least one of the normal effector functions or responses of immune cells, such as engineered T cells engineered to express CAR.
- CAR induces the function of T cells, such as cytolytic activity or helper T cell activity, such as secretion of cytokines or other factors.
- a truncated portion of an intracellular signal transduction domain of an antigen receptor moiety or a costimulatory molecule is used in place of a complete immunostimulatory chain, for example, if it transduces effector function signals.
- the intracellular signal transduction domain includes the cytoplasmic sequence of T cell receptors (TCRs), and in some aspects, also those co-receptors that occur in nature acting in concert with these receptors to Signal transduction is initiated after antigen receptor binding.
- TCRs T cell receptors
- the CAR does not include components for generating a co-stimulatory signal.
- other CARs are expressed in the same cell and provide components for generating a second or costimulatory signal.
- T cell activation is described as mediated by two types of cytoplasmic signal transduction sequences: those that initiate antigen-dependent primary activation by TCR (primary cytoplasmic signal transduction sequences), and in an antigen-independent manner Those that act to provide a second or costimulatory signal (second cytoplasmic signal transduction sequence).
- the CAR includes one or both of such signal transduction components.
- the antibody portion of the chimeric antigen receptor (e.g., CAR) further includes a signal peptide, such as a signal peptide including CD8 or a variant thereof, such as comprising the amino acid sequence shown in SEQ ID NO: 35, or IDNO: 35 shows at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% Or more sequence identity amino acid sequences.
- the CAR includes a major cytoplasmic signal transduction sequence that modulates the initial activation of the TCR complex.
- the first cytoplasmic signal transduction sequence acting in a stimulating manner may comprise a signal transduction motif, which is known as an immunoreceptor tyrosine-based activation motif or ITAM.
- ITAM include first cytoplasmic signal transduction sequences, including those derived from: TCR ⁇ , FcR ⁇ , FcR ⁇ , CD3 ⁇ , CD3 ⁇ , CDS, CD22, CD79a, CD79b, and CD66d.
- the cytoplasmic signal transduction molecule in the CAR comprises a cytoplasmic signal transduction domain, which is partially or derived from a sequence of CD3 ⁇ .
- the CAR includes a transmembrane portion of a costimulatory receptor and / or a signal transduction domain, such as CD28, CD137, OX40, DAP10, and ICOS. In some aspects, the same CAR includes both activating and co-stimulating portions.
- the activation domain is included in one CAR and the co-stimulatory component is provided by another CAR that recognizes another antigen.
- the CAR comprises an activated or stimulated CAR, a co-stimulated CAR, all of which are expressed on the same cell (see WO2014 / 055668).
- the cells include one or more of a stimulating or activating CAR and / or a co-stimulating CAR.
- the cell further comprises an inhibitory CAR (iCAR, see Fedorov et al., Sci. Transl.
- identifying cells other than those associated with and / or specific to a disease or disorder CAR, thereby activating signals delivered by the disease-targeting CAR, are reduced or inhibited by inhibiting the binding of CAR to its ligand, such as reducing off-target effects.
- the intracellular signal transduction portion of the chimeric antigen receptor, such as CAR comprises a CD3 ⁇ intracellular domain and a co-stimulatory signal transduction region.
- the intracellular signal transduction domain comprises a CD28 transmembrane and a signal transduction domain connected to a CD3 (eg, CD3- ⁇ ) intracellular domain.
- the intracellular signal transduction domain comprises a chimeric CD28 and / or CD137 (4-1BB, TNFRSF9) co-stimulatory domain that is linked to a CD3 ⁇ intracellular domain.
- the CAR encompasses one or more, for example, two or more, a co-stimulatory domain and an activation domain, for example, an initial activation domain in a cytoplasmic portion.
- exemplary CARs include the intracellular portions of CD3- [zeta], CD28, and CD137.
- the CAR is referred to as a first, second, and / or third generation CAR.
- the first-generation CAR is a CAR that provides only the CD3 chain-inducing signal upon antigen binding;
- the second-generation CAR is a CAR that provides such signals and co-stimulatory signals, including, for example, from co-stimulatory receptors ( (Eg, CD28 or CD137), a CAR of an intracellular signal transduction domain;
- a third-generation CAR is a CAR that includes multiple co-stimulatory domains of different co-stimulatory receptors.
- the chimeric antigen receptor includes an extracellular portion containing an antibody or antibody fragment. In some aspects, a chimeric antigen receptor includes an extracellular portion containing an antibody or fragment and an intracellular signal transduction domain. In some embodiments, the antibody or fragment comprises a scFv, and the intracellular domain comprises ITAM. In some aspects, the intracellular signal transduction domain comprises a signal transduction domain of the zeta chain of the CD3-zeta chain. In some embodiments, the chimeric antigen receptor includes a transmembrane domain that connects an extracellular domain and an intracellular signal transduction domain. In some aspects, the transmembrane domain comprises a transmembrane portion of CD28.
- the chimeric antigen receptor contains an intracellular domain of a T-cell costimulatory molecule.
- the extracellular domain and the transmembrane domain can be connected directly or indirectly.
- the extracellular domain and the transmembrane pass a linker sequence.
- the receptor comprises an extracellular portion of a molecule that is a derived source of a transmembrane domain, such as a CD28 extracellular portion.
- the chimeric antigen receptor comprises an intracellular domain derived from a T cell co-stimulatory molecule or a functional variant thereof, such as between a transmembrane domain and an intracellular signal transduction domain.
- the T-cell costimulatory molecule is CD28 or 41BB.
- a CAR contains an antibody, such as an antibody fragment, is or contains a transmembrane domain of a CD28 or a functional variant thereof, and a cell containing a signal transduction moiety or a functional variant of CD28 Internal signal transduction domain, and the signal transduction part of CD3 ⁇ or a functional variant thereof.
- the CAR contains an antibody, such as an antibody fragment, is a transmembrane domain comprising or containing a CD28 transmembrane portion or a functional variant thereof, and an intracellular signal comprising a signal transduction moiety or functional variant of CD137 The transduction domain, as well as the signal transduction part of CD3 ⁇ or a functional variant thereof.
- the receptor further comprises a linker sequence comprising a portion of an Ig molecule (eg, a human Ig molecule), such as an Ig hinge, such as an IgG4 hinge, such as a hinge-only linker sequence.
- the chimeric antigen receptor has: (i) an antibody that specifically recognizes a tumor antigen, a transmembrane region of CD28 or CD8, a costimulatory signal domain of CD28, and CD3 ⁇ ; or (ii) specific Antibodies that sexually recognize tumor antigens, transmembrane regions of CD28 or CD8, co-stimulatory signal domains of CD137, and CD3 ⁇ ; or (iii) antibodies that specifically recognize tumor antigens, transmembrane regions of CD28 or CD8, and co-stimulus signals of CD28 Domain, CD137 co-stimulatory signal domain, and CD3 ⁇ .
- the CAR includes an antibody, such as an antibody fragment, including scFv, a linker sequence, such as a linker sequence that contains a portion of an immunoglobulin molecule, such as a hinge region and / or one or more heavy chain molecule constant regions,
- an Ig-hinge-containing linking sequence a transmembrane domain containing all or part of a CD28-derived transmembrane domain, a CD28-derived intracellular signal domain, and a CD3 ⁇ signal transduction domain.
- the CAR includes an antibody or fragment, such as a scFv, a linker sequence, such as any Ig-hinge-containing linker sequence, a CD28-derived transmembrane domain, a CD137-derived intracellular signal transduction domain, and a CD3 ⁇ -derived signal Transduction domain.
- a linker sequence such as any Ig-hinge-containing linker sequence
- CD28-derived transmembrane domain such as any Ig-hinge-containing linker sequence
- CD137-derived intracellular signal transduction domain such as CD137-derived intracellular signal transduction domain
- CD3 ⁇ -derived signal Transduction domain such as any Ig-hinge-containing linker sequence
- the methods described herein include administering to the subject an adoptive cell or an immune effector cell. In some embodiments, the methods described herein include administering to the subject two or more adoptive cells or immune effector cells against the same tumor antigen in different courses of treatment. In some embodiments, the methods described herein include administering to the subject two or more adoptive cells or immune effector cells to different tumor antigens in different courses of treatment. In some embodiments, the methods described herein include administering to the subject two or more adoptive cells or immune effector cells against the same epitope of the same tumor antigen in different courses of treatment.
- the methods described herein include administering to the subject two or more adoptive cells or immune effector cells to different epitopes of the same tumor antigen in different courses of treatment. In some embodiments, the methods described herein include administering two or more adoptive cells or immune effector cells to the subject in different courses of treatment to treat a tumor at the same site. In some embodiments, the methods described herein include administering to the subject two or more adoptive cells or immune effector cells in different courses of treatment to treat tumors at different sites. In some embodiments, at least one of the adoptive cells or immune effector cells employed by the methods described herein targets BCMA CAR-T cells.
- At least one of the adoptive cells or immune effector cells employed in the methods described herein is a BCMA-targeting CAR-T cell described herein.
- a person skilled in the art for example, a clinician, can decide the number of administrations and doses of the BCMA-CAR-T cells of the present invention according to the situation of the previous treatment.
- the cells provided by the methods described herein are immune effector cells that express a chimeric antigen receptor.
- the cells are generally mammalian cells, and are typically human cells.
- the cells are derived from blood, bone marrow, lymph, or lymphoid organs and are cells of the immune system, such as innate or adaptive immune cells, such as bone marrow or lymphoid cells, including lymphocytes, typically T cells and / Or NK cells.
- Other exemplary cells include stem cells, such as multipotent and pluripotent stem cells, including induced pluripotent stem cells (iPSC).
- Cells are generally primary cells, such as those cells isolated directly from the subject and / or isolated and frozen from the subject.
- the cells include one or more subgroups of T cells or other cell types, such as whole T cell populations, CD4 + cells, CD8 + cells and subgroups thereof, such as by function, activation status, maturity, differentiation potential, Amplification, recycling, localization, and / or persistence, antigen specificity, antigen receptor type, presence in a particular organ or compartment, marker or cytokine secretion profile, and / or those defined by the degree of differentiation.
- the cells may be allogeneic and / or autologous. Methods include ready-made methods.
- cells are pluripotent and / or multipotent, such as stem cells, such as induced pluripotent stem cells (iPSC).
- the method includes isolating cells from a subject, preparing, processing, culturing, and / or engineering them, and reintroducing them into the same patient before or after cryopreservation.
- Subtypes and subpopulations of T cells and / or CD4 + and / or CD8 + T cells include: primary T (TN) cells, effector T cells (TEFF), memory T cells and their subtypes, such as stem cell memory T (TSCM) , Central memory T (TCM), effector memory T (TEM), or eventually differentiated effector memory T cells, tumor-infiltrating lymphocytes (TIL), immature T cells, mature T cells, helper T cells, cytotoxicity T cells, mucosa-associated non-variant T (MAIT) cells, naturally occurring and adoptively regulated T (Treg) cells, helper T cells such as TH1 cells, TH2 cells, TH3 cells, TH17 cells, TH9 cells, TH22 Cells, follicular helper T cells, ⁇ / ⁇ T cells, and ⁇ / ⁇ T cells.
- TN primary T
- TEFF effector T cells
- TCM stem cell memory T
- TCM Central memory T
- TEM
- the cells are natural killer (NK) cells.
- the cells are monocytes or granulocytes, for example, bone marrow cells, macrophages, neutrophils, dendritic cells, mast cells, eosinophils, and / or basophils granulocyte.
- the cell comprises one or more nucleic acids introduced by genetic engineering, and thereby expresses a recombinant or genetically engineered product of the nucleic acid.
- the nucleic acid is heterologous, that is, typically not present in a cell or a sample obtained from the cell, such as a sample obtained from another organism or cell, such as a cell that is not normally engineered And / or such cell-derived organisms.
- the nucleic acid is not naturally occurring, such as a nucleic acid is not found in nature, including a chimeric combination comprising nucleic acids encoding various domains from multiple different cell types.
- the invention also provides methods, compositions and kits for generating genetically engineered cells expressing a chimeric antigen receptor.
- Genetic engineering generally involves introducing a nucleic acid encoding the recombined or engineered portion into a cell, such as through viral transduction, electrotransduction, or the like.
- gene transfer is performed by first stimulating a cell, for example, by combining it with a stimulus that induces a response, such as proliferation, survival, and / or activation, for example, by a cytokine or The expression of the activation marker is detected, and then the activated cells are transduced and expanded in culture to an amount sufficient for clinical use.
- the cells are also engineered to promote the expression of cytokines or other factors.
- cytokines e.g., CAR
- Various methods for introducing genetically engineered components, such as antigen receptors (e.g., CAR) are well known and can employ the methods and compositions provided herein. Exemplary methods include those used to transfer a nucleic acid encoding a receptor, including by viruses, such as retroviruses or lentiviruses, transduction, transposons, and electroporation.
- a recombinant infectious virus particle is used to transfer the recombinant nucleic acid into a cell, for example, a vector derived from simian virus 40 (SV40), adenovirus, adeno-associated virus (AAV).
- SV40 simian virus 40
- AAV adeno-associated virus
- a recombinant lentiviral vector or a retroviral vector such as a gamma-retroviral vector, is used to transfer the recombinant nucleic acid into T cells.
- the preparation of the engineered cells includes one or more culture and / or one or more preparation steps.
- Cells used to introduce a nucleic acid encoding a transgenic receptor can be isolated from a sample (eg, a biological sample, such as a sample obtained from or derived from a subject).
- a sample eg, a biological sample, such as a sample obtained from or derived from a subject.
- the subject from which the cells are isolated is a subject who has a certain disease or disorder or who requires or will be administered a cell therapy.
- the subject is a person in need of specific therapeutic intervention, for example, a person in need of adoptive cell therapy or effector cell therapy, and the cells used for the therapy are isolated, processed, and / or engineered .
- the cell is a primary cell, such as a primary human cell.
- the samples include tissue, body fluids, and other samples taken directly from the subject, as well as obtained from one or more processing steps, such as isolation, centrifugation, genetic engineering (e.g., transduction with viral vectors), washing, and / or Incubate the samples.
- the biological sample may be a sample obtained directly from a biological source or a processed sample.
- Biological samples include, but are not limited to, body fluids such as blood, plasma, serum, cerebrospinal fluid, synovial fluid, urine, and sweat, tissue and organ samples, including processed samples derived from them.
- Exemplary samples include whole blood, peripheral blood mononuclear cells (PBMC), white blood cells, bone marrow, thymus, tissue biopsy, tumor, leukemia, lymphoma, lymph nodes, bowel-associated lymphoid tissue, mucosa-associated lymphoid tissue, spleen , Other lymphoid tissue, liver, lung, stomach, intestine, colon, kidney, pancreas, breast, bone, prostate, cervix, testis, ovary, tonsil or other organ, and / or cells derived from it.
- samples include samples from autologous and allogeneic sources.
- the isolation of the cells includes one or more steps of preparation and / or affinity-based cell isolation.
- the cells are washed, centrifuged, and / or incubated in the presence of one or more substances, for example, to remove unwanted components, enrich the desired components, lyse or remove Sensitive cells.
- cells are isolated based on one or more properties, such as density, adhesion properties, size, sensitivity and / or resistance to specific components. In some examples, for example, by apheresis or leukapheresis, cells from the subject's circulating blood are obtained.
- the sample includes lymphocytes, including T cells, monocytes, granulocytes, B cells, other nucleated blood leukocytes, red blood cells, and / or platelets.
- blood cells collected from the subject are washed, for example, to remove a portion of plasma, and the cells are placed in a suitable buffer or medium for subsequent processing steps.
- the cells are washed with phosphate buffered saline (PBS).
- PBS phosphate buffered saline
- the cleaning solution is deficient in calcium and / or magnesium and / or many or all divalent cations.
- the washing step is performed by a semi-automatic "flow-through" centrifugation method (eg, COBE 2991 Cell Processor, BaXter) according to the manufacturer's instructions.
- the washing step is performed by end-cut filtration (TFF) according to the manufacturer's instructions.
- the cells after washing, the cells are resuspended in a variety of biocompatible buffers, for example, Ca ++ / Mg ++ PBS-free.
- biocompatible buffers for example, Ca ++ / Mg ++ PBS-free.
- blood cell sample components are removed and the cells are resuspended directly in the culture medium.
- the method comprises a density-based cell separation method, for example, obtaining peripheral blood cells by lysing red blood cells or not lysing red blood cells and preparing peripheral blood or single sample or leukapheresis samples by Percoll or Ficoll gradient centrifugation. Nuclear cells (PBMC).
- PBMC Nuclear cells
- the method of isolation includes separating different cell types based on the expression or presence of one or more specific molecules in a cell, such as surface markers, such as surface proteins, intracellular markers, or nucleic acids. In some embodiments, any known method for separation based on such markers can be used. In some embodiments, the separation is an affinity-based or an immunoaffinity-based separation.
- the isolating comprises isolating cells and cell populations based on the expression or expression level of one or more markers (typically cell surface markers) of the cell, for example, by specifically binding thereto
- a marker-like antibody or binding partner is incubated, usually followed by a washing step, and cells that have bound the antibody or binding partner are isolated from those cells that have not yet bound to the antibody or binding partner.
- isolation steps may be based on positive selection, where cells that have bound the agent are retained for further use, and / or negative selection, where cells that have not yet bound to the antibody or binding partner are retained. In some examples, both parts are reserved for further applications. In some aspects, negative selection may be particularly useful when there are no antibodies available to specifically identify cell types in a heterogeneous population, so isolation is best based on markers expressed by cells different from the desired population .
- the isolation need not result in 100% enrichment or removal of a particular cell population or cells expressing a particular marker.
- a particular type of cell being selected or enriched refers to an increase in the number or percentage of the cells, but need not result in the complete absence of cells that do not express the marker.
- negatively selecting, removing, or depleting specific types of cells, such as those expressing markers refers to reducing the number or percentage of the cells, but not necessarily causing complete removal of all such cells.
- multiple rounds of separation steps are performed, where a portion of positive or negative selection from one step is subjected to another separation step, such as a subsequent positive or negative selection.
- a single isolation step simultaneously consumes cells that express multiple markers, such as by incubating the cells with multiple antibodies or binding partners that are each specific for a negatively selected targeted marker.
- multiple cell types can be positively selected simultaneously by incubating the cells with multiple antibodies or binding partners expressed on various cell types.
- a specific subpopulation of T cells such as one or more surface marker positive cells or cells expressing high levels of one or more surface markers, for example, CD3 +, CD28 +, CD62L +, CCR7 + , CD27 +, CD127 +, CD4 +, CD8 +, CD45RA + and / or CD45RO + T cells are isolated by positive or negative selection techniques.
- CD3 + and CD28 + T cells can be positively selected using CD3 / CD28-linked magnetic beads (eg, DYNA beads M-450CD3 / CD28T cell amplifier).
- CD3 / CD28-linked magnetic beads eg, DYNA beads M-450CD3 / CD28T cell amplifier.
- the isolation is performed by enriching a specific cell population by positive selection or depleting a specific cell population by negative selection.
- positive or negative selection is accomplished by incubating cells with one or more antibodies or other binding agents that specifically bind to one or more surface markers, the one or more surfaces Markers are expressed on positively or negatively selected cells (marker +) or at relatively high levels (marker high), respectively.
- T cells are isolated from a PBMC sample by negative selection of a marker (eg, CD14) expressed on non-T cells (eg, B cells, monocytes, or other blood leukocytes).
- a CD4 + or CD8 + selection step is used to isolate helper CD4 + and CD8 + cytotoxic T cells.
- Such CD4 + and CD8 + populations can be further sorted into subpopulations by positive or negative selection of markers expressed on one or more primary, memory, and / or effector T cell subpopulations or expressed to a relatively high degree. group.
- the CD8 + cells are further enriched or depleted for primary, central memory, effector memory, and / or central memory stem cells, such as by positive or negative selection based on surface antigens associated with corresponding subpopulations.
- enrichment for central memory T (TCM) cells is performed to increase efficacy, such as to improve long-term survival, expansion, and / or implantation after administration. In some aspects, it is in such sub-types
- the group is particularly strong. See Terakura et al. (2012) Blood. 1: 72-82; Wang et al. (2012) J Immunother. 35 (9): 689-701.
- TCM-enriched CD8 + T cells are combined with CD4 + T cells to further enhance efficacy.
- memory T cells are present in the CD62L + and CD62L- subsets of CD8 + peripheral blood lymphocytes.
- PBMCs can be enriched or consumed against CD62L-CD8 + and / or CD62L + CD8 + portions, for example using anti-CD8 and anti-CD62L antibodies.
- the enrichment for central memory T (TCM) cells is based on CD45RO, CD62L, CCR7, CD28, CD3, and / or CD127 positive or high surface expression; in some aspects, it is based on CD45RA and / or granules Cells expressing Enzyme B or highly expressed were negatively selected.
- isolation of the CD8 + population enriched for TCM cells is performed by depleting cells expressing CD4, CD14, CD45RA, and enriching for cells that are being selected or targeted for CD62L.
- the enrichment for central memory T (TCM) cells is performed by starting with a negative portion of cells selected based on CD4 expression, which performs negative selection based on the expression of CD14 and CD45RA, and positive selection based on CD62L. In some aspects, such selections occur simultaneously, and in other aspects, such selections occur sequentially in a certain order. In some aspects, the same CD4 expression-based selection step is used to prepare a CD8 + cell population or subpopulation, and also to generate a CD4 + cell population or subpopulation, thereby retaining the positive and negative portions from the CD4-based separation, and optionally After one or more further positive or negative selection steps, for subsequent steps of the method.
- CD4 + cell selection is performed on a PBMC sample or other blood leukocyte sample, with the negative and positive portions retained. Then, negative selection is performed on the negative part based on the expression of CD14 and CD45RA or CD19, and positive selection is performed based on a central memory T cell characteristic marker, such as CD62L or CCR7, wherein the positive and negative selection are performed in a certain order.
- a central memory T cell characteristic marker such as CD62L or CCR7
- helper CD4 + T cells were sorted into primary, central memory, and effector cells.
- CD4 + lymphocytes can be obtained by standard methods.
- the original CD4 + T lymphocytes are CD45RO-, CD45RA +, CD62L +, CD4 + T cells.
- the central memory CD4 + cells are CD62L + and CD45RO +.
- the effector CD4 + cells are CD62L- and CD45RO-.
- monoclonal antibody mixtures typically include antibodies against CD14, CD20, CD11b, CD16, HLA-DR, and CD8.
- the antibody or binding partner is bound to a solid support or matrix, such as magnetic or paramagnetic beads, to allow isolation of cells for positive and / or negative selection.
- the method of preparation includes a freezing step, such as freezing the cells before or after isolation, incubation, and / or engineering.
- the freezing and subsequent thawing steps remove granulocytes and, to some extent, monocytes in the cell population.
- the cells are suspended in a frozen solution after a washing step to remove plasma and platelets.
- any of a variety of known frozen solutions and parameters can be used.
- the cells are generally frozen to -80 ° C or -90 ° C according to a predetermined procedure or principle, such as a rate of 1 ° / min, by a program-controlled cooling device, and stored in the vapor phase of a liquid nitrogen storage tank.
- a predetermined procedure or principle such as a rate of 1 ° / min
- provided methods include breeding, incubating, culturing, and / or genetic engineering steps.
- methods are provided for incubating and / or engineering depleted cell populations and culture starting compositions.
- the cell population is incubated in a culture initiation composition.
- Incubation and / or engineering can be performed in culture vessels, such as units, chambers, wells, columns, tubes, tube sets, valves, vials, culture dishes, bags, or other containers used to culture or grow cells.
- the cells are incubated and / or cultured prior to or with genetic engineering.
- the incubation step may include culturing, incubating, stimulating, activating, and / or propagating.
- the cells or compositions are incubated in the presence of a stimulating condition or stimulating agent.
- a stimulating condition or stimulating agent include those designed to induce cell proliferation, reproduction, activation, and / or survival in a population to mimic antigen contact, and / or trigger cells for genetic engineering, such as those used to introduce recombinant antigen receptors.
- the conditions may include one or more of the following: specific media, temperature, oxygen content, carbon dioxide content, time, reagents, such as nutrients, amino acids, antibiotics, ions, and / or stimulating factors such as cytokines, Chemokines, antigens, binding partners, fusion proteins, recombinant soluble receptors, and any other substances designed to maintain the state of activated cells.
- the stimulating conditions or agents include one or more substances, eg, ligands, which are capable of activating the intracellular signal transduction domain of the TCR complex.
- the substance turns on or initiates a TCR / CD3 intracellular signal transduction cascade in T cells.
- substances may include antibodies, such as those specific for TCR components and / or costimulatory receptors, such as anti-CD3, anti-CD28, for example, which bind to a solid support, such as beads, and / or an Or multiple cytokines.
- the amplification method may further include the step of adding anti-CD3 and / or anti-CD28 antibodies to the culture medium (e.g., at a concentration of at least about 0.5 ng / ml).
- the stimulant includes 1L-2 and / or IL-15 and / or IL-7 and / or IL-21, for example, IL-2 at a concentration of at least about 10 units / mL.
- the incubation is in accordance with techniques such as US Patent No. 6,040,177 to Riddell et al., Klebanoff et al., (2012) J Immunother. 35 (9): 651-660, Terakura et al., (2012) Blood. 1: 72- 82 and / or those described in Wang et al. (2012) J Immunother. 35 (9): 689-701.
- the T cell population is expanded by adding to feeder cells of the culture initiation composition, such as non-dividing peripheral blood mononuclear cells (PBMC), (eg, to target the initial population to be expanded).
- PBMC peripheral blood mononuclear cells
- Each T lymphocyte, the resulting cell population comprises at least about 5, 10, 20, or 40 or more PBMC feeder layer cells); and the culture is incubated (eg, a time sufficient to expand the number of T cells).
- the non-dividing feeder layer cells can include gamma-irradiated PBMC feeder layer cells.
- the PBMC is irradiated with gamma rays in the range of about 3000-3600 rads to prevent cell division.
- the feeder layer cells are added to the culture medium before the population of T cells is added.
- the stimulation conditions include a temperature suitable for human T lymphocyte growth, for example, at least about 25 degrees Celsius, generally at least about 30 degrees Celsius, and generally or about 37 degrees Celsius.
- the incubating may further include adding non-dividing EBV-transformed lymphoblastoid cells (LCL) as feeder cells.
- LCL can be irradiated with gamma rays in the range of about 6000-10000 rad.
- the LCL feeder layer cells are provided in any suitable amount, such as a ratio of LCL feeder layer cells to initial T lymphocytes is at least about 10: 1.
- antigen-specific T cells such as antigen-specific CD4 + and / or CD8 + T cells
- antigen-specific T cell lines or clones can be produced against cytomegalovirus antigens by isolating T cells from an infected subject and stimulating the cells in vitro with the same antigen.
- compositions and preparations are provided.
- compositions including cells for administration including pharmaceutical compositions and formulations, such as unit dosage form compositions from a number of cells for administration that contain a given dose or portion thereof.
- the pharmaceutical compositions and formulations generally include one or more optional pharmaceutically acceptable carriers or excipients.
- the composition includes at least one other therapeutic agent.
- pharmaceutical formulation refers to a formulation in a form that allows the biological activity of the active ingredient contained therein to be effective, and contains no additional ingredients with unacceptable toxicity to the subject to be administered the formulation.
- “Pharmaceutically acceptable carrier” refers to an ingredient in a pharmaceutical formulation that is not the active ingredient and is non-toxic to the subject.
- Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, or preservatives.
- the selection of the carrier is determined in part by the particular cell and / or method of administration. Therefore, there are many suitable formulations.
- the pharmaceutical composition may include a preservative. Suitable preservatives may include, for example, methyl paraben, propyl paraben, sodium benzoate, and benzalkonium chloride. In some aspects, a mixture of two or more preservatives is used. Preservatives or mixtures thereof are typically present in an amount of from about 0.0001% to about 2% (based on the total weight of the composition). Carriers are described, for example, in Remington's Pharmaceutical Sciences, 16th edition, edited by Osol, A. (1980).
- pharmaceutically acceptable carriers are generally non-toxic to the recipient, including but not limited to: buffers such as phosphates, citrates and other organic acid buffers; antioxidants, including ascorbic acid and Methionine; Preservatives (such as stearyl dimethyl benzyl ammonium chloride; hexahydrocarbon quaternary ammonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; p-hydroxyl Alkyl benzoates, such as methyl or propyl parabens; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) ) Polypeptides; proteins such as serum albumin, gelatin or immunoglobulin; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, aspara
- the composition comprises a buffering agent.
- Suitable buffering agents include, for example, citric acid, sodium citrate, phosphoric acid, potassium phosphate, and various other acids and salts.
- a mixture of two or more buffering agents is used.
- the buffer or mixture thereof is typically present in an amount of from about 0.001% to about 4% (based on the total weight of the composition).
- the formulation may include an aqueous solution.
- the formulation or composition may also contain more than one active ingredient, which may be used for a particular indication, disease or condition to be treated with the cells, preferably those having complementary activity to the cells, wherein the corresponding activity
- the agents do not negatively affect each other.
- active ingredients are suitably present in combination in amounts that are effective for the purpose intended.
- the pharmaceutical composition further comprises other pharmaceutically active substances or drugs, such as chemotherapeutic agents, for example, asparaginase, busulfan, carboplatin, cisplatin, daunorubicin, doxorubicin Bixin, fluorouracil, gemcitabine, hydroxyurea, methotrexate, paclitaxel, rituximab, vinblastine, and / or vincristine.
- chemotherapeutic agents for example, asparaginase, busulfan, carboplatin, cisplatin, daunorubicin, doxorubicin Bixin, fluorouracil, gemcitabine, hydroxyurea, methotrexate, paclitaxel, rituximab, vinblastine, and / or vincristine.
- the pharmaceutical composition comprises an amount effective to treat or prevent a disease or disorder, such as a therapeutically effective or preventive effective amount of cells.
- a disease or disorder such as a therapeutically effective or preventive effective amount of cells.
- therapeutic or prophylactic efficacy is monitored by periodically assessing treated subjects. The required dose may be delivered to the cells by a single pill, the cells by multiple pills or by continuous infusion.
- the composition comprises an amount effective to reduce the burden of a disease or disorder, and / or an amount that does not cause CRS or severe CRS in a subject and / or an amount that achieves any other result of the methods described herein Cell.
- the cells and compositions can be administered using standard administration techniques, formulations and / or devices.
- the administration of the cells may be autologous or heterologous.
- immunosuppressive cells or progenitor cells can be obtained from one subject and administered to the same subject or different compatible subjects.
- Peripheral blood-derived immunosuppressive cells or their progeny eg, derived in vivo, ex vivo, or in vitro
- a therapeutic composition e.g., a pharmaceutical composition containing genetically modified immunosuppressive cells
- it is usually formulated as an injectable form (solution, suspension, emulsion) in a unit dosage form.
- Formulations include those for oral, intravenous, intraperitoneal, subcutaneous, pulmonary, transdermal, intramuscular, intranasal, mucosal, sublingual or suppository administration.
- the cell population is administered parenterally.
- parenteral as used herein includes intravenous, intramuscular, subcutaneous, rectal, vaginal, and intraperitoneal administration.
- the cells are administered to a subject by intravenous, intraperitoneal or subcutaneous injection using peripheral systemic delivery.
- the composition is provided in the form of a sterile liquid formulation, for example, an isotonic aqueous solution, suspension, emulsion, dispersion or viscous composition, which in some aspects can be buffered to a selected pH.
- a sterile liquid formulation for example, an isotonic aqueous solution, suspension, emulsion, dispersion or viscous composition, which in some aspects can be buffered to a selected pH.
- Liquid formulations are generally easier to prepare than gels, other viscous compositions, and solid compositions.
- liquid compositions are somewhat easier to administer, especially by injection.
- the viscous composition can be formulated within a suitable viscosity range to provide longer contact time with a particular tissue.
- Liquid or viscous compositions may include a carrier, which may be a solvent or dispersion medium, containing, for example, water, saline, phosphate buffered saline, polyhydroxy compounds (e.g., glycerol, propylene glycol, liquid polyethylene glycol), and Suitable mixture.
- a carrier such as water, saline, phosphate buffered saline, polyhydroxy compounds (e.g., glycerol, propylene glycol, liquid polyethylene glycol), and Suitable mixture.
- Sterile injectable solutions can be prepared by incorporating the cells into a solvent, such as with a suitable carrier, diluent, or excipient such as sterile water, physiological saline, glucose, dextrose, and the like.
- composition may contain auxiliary substances such as wetting, dispersing, or emulsifying agents (e.g., methyl cellulose), pH buffering agents, gelling or viscosity enhancing additives, preservatives, flavoring agents, and / or pigments, depending on Desired route of administration and preparation.
- auxiliary substances such as wetting, dispersing, or emulsifying agents (e.g., methyl cellulose), pH buffering agents, gelling or viscosity enhancing additives, preservatives, flavoring agents, and / or pigments, depending on Desired route of administration and preparation.
- emulsifying agents e.g., methyl cellulose
- pH buffering agents e.g., methyl cellulose
- gelling or viscosity enhancing additives e.g., preservatives, flavoring agents, and / or pigments, depending on Desired route of administration and preparation.
- preservatives e.g., methyl cellulose
- flavoring agents e.
- the invention also provides articles of manufacture, such as kits and devices, for administering cells to a subject according to the provided methods for adoptive cell therapy or immune effector cell therapy, and for storing and administering the cells and compositions.
- Articles of manufacture include one or more containers, typically multiple containers, packaging materials, and labels or packaging inserts in conjunction with or on one or more containers and / or packaging, and generally include instructions for administering cells to a subject.
- a container typically contains the cells to be administered, for example, one or more unit doses thereof.
- Articles of manufacture generally include multiple containers, each containing a single unit dose of cells.
- the unit dose may be the amount or number of cells to be administered to the subject in the previous course of immune effector cells or twice (or more) the number of cells to be administered in the first or subsequent course of immune effector cells. It may be the lowest dose or the lowest possible dose to the cells associated with the method of administration to the subject.
- the unit dose is the number of cells or the minimum number of cells that will be administered in a unit dose to any subject with a particular disease or disorder in accordance with the methods of the invention.
- a unit dose may include a minimum amount of cells that will be administered to a subject with a lower body weight and / or a lower disease burden, such as administering one or In some cases more than one unit dose and one or more unit doses are given to a given subject in one or more immune effector cells during a later course of treatment, for example, as provided.
- the number of cells in a unit dose is the number of chimeric antigen receptor-expressing or CAR-expressing cells that need to be administered to a particular subject, such as a cell-derived subject, with a prior course of immune effector cells or Number of cells.
- the cells are derived from a subject to be treated by the methods provided herein.
- each container individually contains a unit dose of cells, for example, including the same or substantially the same number of cells.
- each container contains the same or about or substantially the same number of cells or chimeric antigen receptor-expressing cells.
- the unit dose comprises less than about 1x10 10 , less than about 1x10 9 , less than about 1x10 8 or less than about 1x10 7 engineered cells, total cells, T cells or PBMC / kg to be treated and / or cell derived Subject.
- Suitable containers include, for example, bottles, vials, syringes, and flexible bags such as freezer bags.
- the container is a bag, for example, a flexible bag, such as those suitable for infusion of cells to a subject, for example, a flexible plastic or PVC bag or EVA or ULPDE, and / or an IV solution bag.
- the bag is sealable and / or sterilizable to provide sterile solutions and delivery of cells and compositions.
- the volume of the container for example, a bag is equal to or about or at least or about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, or 1000 ml Volume, such as equal to or about 10 to equal to or about 100 mL or equal to or about 10 to equal to or about 500 mL volume.
- a container for example, a bag is and / or is made of a material that is stable and / or provides stable storage and / or maintenance of cells at one or more different temperatures, such as at low temperatures, for example, low At or about or equal to or about -20 ° C, -80 ° C, -120 ° C, 135 ° C, -196 ° C and / or a temperature suitable for cryopreservation, and / or other temperatures, such as a temperature suitable for freezing and thawing cells and Body temperature, such as equal to or about 37 ° C or -38 ° C, or -39 ° C, or -40 ° C, to allow freezing and thawing before treatment, for example, at the subject's site or treatment site.
- temperatures such as at low temperatures, for example, low At or about or equal to or about -20 ° C, -80 ° C, -120 ° C, 135 ° C, -196 ° C and / or a temperature suitable for cry
- the container can be made from various materials such as glass or plastic.
- the container has one or more ports, for example, a sterile immersion port, for example, for connecting to one or more tubes through a tube or catheter, for example, for intravenous or other infusion and / or For connection for purposes of transfer from and to other containers, such as cell culture and / or storage bags or other containers.
- exemplary containers include freezer bags, intravenous solution bags, vials, including those with stopper caps that are pierceable by injection needles.
- the article of manufacture may also include a package insert or label, one or more of which display usage information and / or instructions.
- the information or instructions show content that may or should be used to treat a particular disease or condition, and / or provide instructions thereon.
- a label or package insert can show the contents of an article to be used to treat a disease or condition.
- the label or package insert provides instructions for treating a subject, e.g., a subject in which the cells have been derived, by including cells administered to the first and one or more immune effector cells in a subsequent course, e.g., A method according to any one of the provided method embodiments.
- the instructions specify that a unit dose is administered in the immune effector cells of the previous course, eg, the contents of a single individual container of the article, and then at a specified time point or within a specified time window and / or detected The presence or absence or amount or extent of one or more factors or results in the subject is followed by the administration of one or more immune effector cells at a later course of treatment.
- the instructions specify the administration of multiple unit doses to a subject by performing a first dose and a continuous dose.
- the first administration comprises delivering one of the unit doses to the subject and the subsequent administration comprises administering one or more of the unit doses to the subject.
- the label or package insert or package includes an identifier to indicate the identity of the subject from which the cells were derived and / or the subject to be administered.
- the cells are derived from a subject to be administered to the cells.
- the identifying information may specify that the cells are to be administered to a particular patient, such information may be present in the packaging material and / or label in the form of a barcode or other coded identifier, or may indicate the subject's name and / or other identifying characteristics.
- the article of manufacture comprises one or more, typically multiple containers containing a composition comprising cells, such as its individual unit dosage form, and also includes one or more other containers containing the composition therein,
- the composition comprises other agents, such as cytotoxic or other therapeutic agents, which will be combined with the cells, for example, administered at the same time or in any order.
- the preparation may also include another or the same container containing a pharmaceutically acceptable buffer. It may also include other materials, such as other buffers, diluents, filters, tubes, needles, and / or syringes.
- package insert refers to the instructions often included in the commercial packaging of therapeutic products, which contain information on the use, use, dosage, administration, combination therapy, contraindications, and / or warnings of the use of such therapeutic products.
- PBMCs Peripheral blood mononuclear cells
- T cells from a human subject with cancer by "mononuclear cell removal-free” and cultured and transduced with a viral vector encoding a chimeric antigen receptor (CAR) Cell
- the chimeric antigen receptor (CAR) specifically binds an antigen expressed by a cancer in a subject, which is a tumor-associated or tumor-specific antigen.
- CAR chimeric antigen receptor
- Cells cryopreserved in freezing infusion medium separate flexible bags, each cell contains a single unit dose, which is about 1 ⁇ 10 5 cells to 1 ⁇ 10 9 cells. Prior to infusion, the cells are maintained at a temperature below about -130 ° C or about below -175 ° C.
- tumor burden can optionally be assessed by measuring the size or quality of a solid tumor, such as by PET or CT scans.
- Resuscitation was performed by warming to about 38 ° C, and the subject was given cells of the immune effector cells of the previous course by multiple infusions.
- the infusion is given intravenously (IV) as a continuous infusion over about 1-20 ml / min.
- the subject undergoes a physical examination and monitors for signs of any toxic or toxic outcome, such as fever, hypotension, hypoxia, neurological disorders or inflammatory cytokines or C-reactive protein (CRP ) Increased serum levels.
- any toxic or toxic outcome such as fever, hypotension, hypoxia, neurological disorders or inflammatory cytokines or C-reactive protein (CRP ) Increased serum levels.
- blood is obtained from the patient in one or more cases, and the level of the serum factor indicating CRS is assessed by ELISA and / or MSD and / or CBA methods .
- the levels of serum factors were compared with the levels of serum factors obtained just prior to the administration of immune effector cells in the previous course. If necessary, give anti-IL6 or other CRS treatments to reduce the symptoms of CRS.
- the presence or absence of an anti-CAR immune response is optionally detected in a subject after administration of a previous course of immune effector cells, such as 1, 2, 3, and / or 4 weeks after the start of administration, for example, by qPCR , ELISA, ELISPOT, cell-based antibody assays and / or mixed lymphocyte reactions.
- the percentage reduction in tumor burden achieved by the previous course of immune effector cells may optionally be measured one or more times after the administration of immune effector cells of the previous course in patients with solid tumors by scanning (such as PET and CT scans), and / Or by quantifying disease-positive cells in the blood or tumor site.
- Subjects are regularly monitored starting with the administration of immune effector cells for the first course of treatment and for several years. During follow-up, measure tumor load, and / or detect CAR-expressing cells by flow cytometry and quantitative polymerase chain reaction (qPCR) to measure the in vivo proliferation and persistence of the administered cells, and / or assess anti- Development of the CAR immune response.
- qPCR quantitative polymerase chain reaction
- a method of preparing an immune effector cell expressing a chimeric antigen receptor refer to, for example, Chinese Patent Application Publication Nos. CN107058354A, CN107460201A, CN105194661A, CN105315375A, CN105713881A, CN106146666A, CN106519037A, CN106554414A, CN105331585A, CN106397593A, CN106467573A, International Patent Application Publication No. WO2018006882A1, The full content disclosed in WO2015172339A8.
- the amino acid sequence of the scFv portion of the chimeric antigen receptor is shown in SEQ ID NO: 27, the nucleotide sequence is shown in SEQ ID NO: 26, and the scFv has SEQ ID The heavy chain variable region shown by NO: 21 and the light chain variable region shown by SEQ ID NO: 20, and the chimeric antigen receptor has the amino acid sequence shown by SEQ ID NO: 36.
- the CAR containing the scFv may also have other intracellular domains. Therefore, the sequence of the CAR may also be the sequence shown in SEQ ID NO: 37 or 38.
- the scFv shown in SEQ ID NO: 27 has HCDR1 shown in SEQ ID NO: 11, HCDR1 shown in SEQ ID NO: 12, HCDR3 shown in SEQ ID NO: 5, and LCDR1 shown in SEQ ID NO: 6. LCDR shown in SEQ ID NO: 7, LCDR3 shown in SEQ ID NO: 10.
- BCMA-positive multiple myeloma are given autologous T cells expressing anti-BCMA chimeric antigen receptor (CAR).
- CAR anti-BCMA chimeric antigen receptor
- T cells were obtained by separating PBMCs from the peripheral blood of the subject, transduced by a viral vector encoding a BCMA-targeting CAR, and performing a large number of amplifications to obtain a BCMA-targeting CAR from a frozen medium preparation -T cells, which were then aliquoted into frozen bags and stored under liquid nitrogen below -175 ° C, and thawed before resuscitation before reinfusion to subjects. .
- tumor necrosis factor alpha TNF ⁇
- IFN ⁇ interferon gamma
- IL-10 IL-2
- IL-6 cytokine release syndrome
- tumor burden can be assessed by assessing the number of cells associated with cancer, such as in the patient's bone marrow or peripheral blood.
- the tumor burden before treatment was assessed by assessing the bone marrow and the percentage of bone marrow blasts was determined. Subjects with at least 5% blasts in the bone marrow are considered to have a morphological disease (MD).
- MD morphological disease
- Cryopreserved anti-BCMA CAR-T cells were resuscitated by warming to about 38 ° C, and the patient was given by a single infusion. Continuous intravenous (IV) infusion was performed within about 2-30 minutes, and the median infusion duration was 5 minutes. .
- the subject After administration of anti-BCMA CAR-T cells, the subject undergoes a physical examination and monitors for signs of any toxic or toxic results, such as fever, hypotension, hypoxia, neurological disorders or inflammatory cytokines or C-reactive protein (CRP) Elevated serum levels.
- any toxic or toxic results such as fever, hypotension, hypoxia, neurological disorders or inflammatory cytokines or C-reactive protein (CRP) Elevated serum levels.
- blood is obtained from the patient one or more times and the level of the serum factor indicating CRS is assessed by ELISA and / or MSD and / or CBA methods. The levels of serum factors were compared with the levels of serum factors obtained just prior to the first dose. If necessary, give anti-IL6 or other CRS treatments to reduce the symptoms of CRS.
- Subjects were monitored regularly after administration of anti-BCMA CAR-T cells for several years. During follow-up, measure tumor burden, and / or detect anti-BCMA CAR-expressing cells by flow cytometry and quantitative polymerase chain reaction (qPCR) to measure the in vivo proliferation and persistence of the administered cells, and / or evaluate Development of anti-CAR immune response.
- qPCR quantitative polymerase chain reaction
- PFS Progression-free survival
- DCR disease control rate
- ORR objective response rate
- OS overall survival
- the subject is a multiple myeloma patient with positive BCMA expression, relapsed or refractory, and is divided into 4 groups to participate.
- the subjects all overexpressed BCMA (the positive rate of BCMA expression was 53% -100%).
- the median duration of multiple myeloma was between 0.3 and 10.7 years, and most were about 5.2 years (range: 0.4 to 10.7 years).
- the median number of chemotherapy treatments was 6 (3-20), and some subjects had previously received stem cell transplants.
- the average plasma cell proportion in the subject's bone marrow was about 25% (range: ⁇ 5% to 85%).
- the subject's disease classification includes IgG ⁇ type, IgA ⁇ type, IgG ⁇ type, ⁇ light chain type, and IgA ⁇ type. So far, the median follow-up time of the subjects was about 135 days (range: 11 to 260 days).
- the first group is the cyclophosphamide low-dose group.
- the pretreatment dose of cyclophosphamide is not higher than 400 mg / m 2 / d (about 190-310 mg / m 2 / d), and about 20 mg / m 2 / d is given. Fludarabine.
- BCMA CAR-T cells were administered to each subject at about 2 ⁇ 10 6 to 2.7 ⁇ 10 6 cells / kg.
- each subject was infused with BCMA CAR-T cells at about 2 ⁇ 10 6 to 2.5 ⁇ 10 6 cells / kg.
- the third group was a low-dose CAR-T group, which was given an anti-BCMA CAR-T cell infusion of less than 1.5 ⁇ 10 6 cells / kg, and the subject was infused with approximately 0.9 ⁇ 10 6 anti-BCMA CAR-T cells. Cells / kg.
- the fourth group was a high-dose CAR-T group, which consisted of 3 patients.
- the subjects in this group were infused with anti-BCMA CAR-T cells at about 2.7 ⁇ 10 6 to 3.3 ⁇ 10 6 cells / kg.
- the day when the subject was administered CAR T cell therapy was designated as day 0.
- Fludarabine and cyclophosphamide can be given on the same day or on different days.
- groups 1 subjects were given fludarabine on days -6, -5, and -4, and cyclophosphamide on days -6, -5, -4, -3, and -2; or Subjects were given fludarabine and cyclophosphamide on -4, -3, and -2; or subjects were given fludarabine and cyclophosphamide on -3, -2, and -1 ; Or subjects were given fludarabine and cyclophosphamide on days -3 and -2.
- subjects were given fludarabine on days -5, -4, -3, and -2, and cyclophosphamide on days -5, -4; or on days -5,- Subjects were given fludarabine on days 4 and -3 and cyclophosphamide on days -5 and -4; or subjects were given fludarabine on days -5, -4, and -3 , And cyclophosphamide on day -5; or fludarabine to subjects on days -4, -3, and -2, and cyclophosphamide on days -4 and -3; or Subjects were given fludarabine, cyclophosphamide on days -3 and -2.
- group 3 subjects were given fludarabine on days -5, -4 and -3, and cyclophosphamide on days -5 and -4.
- group 4 subjects were given fludarabine on days -6, -5, -4, and -3, and cyclophosphamide on days -6 and -5; or on days -3 and- Subjects were given fludarabine, cyclophosphamide on day 2; or subjects were given fludarabine, cyclophosphamide on days -3, -2, and -1
- the dosage of each group is shown in Table 1.
- the dosages of fludarabine, cyclophosphamide and CAR-T cells indicated in the table are the total dosages.
- Probe783-P1 for the nucleotide sequence, see SEQ ID NO: 42
- the upstream primer sequence was: Primer783P1 -F1 (see SEQ ID NO: 43 for the nucleotide sequence); Primer783P1-R3 (see SEQ ID NO: 44 for the nucleotide sequence) of the downstream primers, detect the copy number of anti-BCMA CAR DNA in peripheral blood until Any two consecutive tests were negative and recorded as continuous survival of anti-BCMA CAR-T cells.
- BCMA CAR-T cells proliferated in all subjects. The cell copy number was detected on the third day, and the peak time was about the third. From 7 to 21 days, it is maintained until 2 to 3 months.
- the number of copies of anti-BCMA CAR DNA in the peripheral blood of patients No. 14, 15, and 16 was tested, and the results showed that the number of CAR-T cells in patient No. 14 reached a peak on the 14th day after CAR-T administration , Can not be detected on day 56; the number of CAR-T cells in patient 15 reached a peak on day 14 after CAR-T administration, and was not detected on day 56; the number of CAR-T cells in patient 16 was on CAR-T It peaked on the 7th day after administration and was undetectable after 6 months.
- the subject's disease status is assessed after administration of anti-BCMA CAR-T cells to assess response to treatment.
- subjects are assessed and monitored for neurotoxicity (neurological complications including symptoms of confusion, aphasia, seizures, convulsions, lethargy and / or altered mental state), graded according to severity (use 1-5 Grade scales, for example, Guido Cavaletti and Paola Marmiroli Nature Reviews 6, 657-666 (December 2010), of which 3 (severe symptoms), 4 (life-threatening symptoms) or 5 (death) are considered severe Neurotoxicity.
- Level 1 (Minor)-Not life threatening, only systemic treatments such as antipyretics and antiemetics (eg fever, nausea, fatigue, headache, myalgia, discomfort);
- Oxygen requirement ⁇ 40%, or high-dose single vasopressor drugs eg noradrenaline ⁇ 20ug / kg / min, dopamine ⁇ 10ug / kg / min, phenylephrine ⁇ 200ug / kg / min, or adrenal Low blood pressure of ⁇ 10ug / kg / min
- vasopressors for example, antidiuretic + one of the above agents, or vasopressors of norepinephrine equal to ⁇ 20ug / kg / min
- Combination of drugs hypotension, or grade 3 organ toxicity, or grade 4 transaminitis (via CTCAE v4.0);
- Level 4 life threatening-requires ventilator support, or level 4 organ toxicity (excluding transaminases);
- Grade 1 (asymptomatic or mild)-mild or asymptomatic
- Level 2 (Medium)-Symptoms that limit daily active activity (ADL), such as cooking, shopping for food or clothes, using the phone, managing money;
- Level 3 severe-symptoms of restricted self-management ADL such as bathing, dressing or undressing, eating, using the toilet, taking medication;
- the CAR shown in SEQ ID NO: 36 is selected as an example. However, it should be understood that other CARs targeting BCMA can also be applied to the technical solution described in this application. CAR as shown in SEQ ID NO: 30, 31, 32, 33, 34, 35, 39, 40, or 41.
- the scFv of the CAR shown in SEQ ID NO: 30, 31, and 32 has the VH shown in SEQ ID NO: 15 and the VL shown in SEQ ID NO: 16 and the CDR regions are: SEQ ID NO: 1 HCDR1 shown in SEQ ID NO: 2 HCDR2 shown in SEQ ID NO: 2 HCDR3 shown in SEQ ID NO: 3 and LCDR1 shown in SEQ ID NO: 6 LCDR2 shown in SEQ ID NO: 7 LCDR2 shown in SEQ ID NO: 8 LCDR3 shown.
- the scFv of the CAR shown in SEQ ID NO: 33, 34, and 35 has the VH shown in SEQ ID NO: 17 and the VL shown in SEQ ID NO: 18, and the CDR regions are: SEQ ID NO: 1 HCDR1 shown in SEQ ID No. 2: HCDR2 shown in SEQ ID NO: 2 HCDR3 shown in SEQ ID NO: 4 and LCDR1 shown in SEQ ID NO: 6 LCDR2 shown in SEQ ID NO: 7 LCDR2 shown in SEQ ID NO: 7 LCDR3 shown.
- the scFv of the CAR shown in SEQ ID NO: 39, 40, 41 (the amino acid sequence is shown in SEQ ID NO: 29, the nucleotide sequence is shown in SEQ ID NO: 28) has SEQ ID ID: 23 VH, and VL shown in SEQ ID NO: 20, CDR regions are HCDR1 shown in SEQ ID NO: 13, HCDR1 shown in SEQ ID NO: 14, HCDR2 shown in SEQ ID NO: 14, and HCDR3 shown in SEQ ID NO: 5, and SEQ IDR NO: 6 LCDR1, SEQ ID NO: 7 LCDR2, SEQ ID NO: 10 LCDR3.
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Abstract
Description
Claims (27)
- 一种治疗BCMA阳性的肿瘤方法,其特征在于,所述方法包括给予受试者至少一个疗程的表达嵌合抗原受体(CAR)的免疫效应细胞,所述免疫效应细胞特异性识别BCMA。
- 根据权利要求1所述的方法,其特征在于,每个疗程的免疫效应细胞的剂量不超过约1x10 9细胞/千克受试者体重或总量不超过约1x10 10细胞;优选地,每个疗程的免疫效应细胞的剂量不超过约1x10 8细胞/千克受试者体重或所述细胞总量不超过约1x10 9,优选的,每个疗程的免疫效应细胞的剂量不超过约1x10 7细胞/千克受试者体重或所述细胞总量不超过约5x10 8。
- 如权利要求1所述的方法,其特征在于,所述每个疗程的免疫效应细胞的总剂量不低于1x10 5;优选的,所述每个疗程的免疫效应细胞的总剂量不低于1x10 6;优选的,所述每个疗程的免疫效应细胞的总剂量不低于1x10 7。
- 如权利要求1所述的方法,其特征在于,给予所述受试者2-5个疗程的所述免疫效应细胞,进一步优选,每个疗程的免疫效应细胞在15天内,分成N次给药,N为不小于1的自然数,在一优选方案中,N为1、2、3或4。
- 如权利要求4所述的方法,其特征在于,当在先给予的免疫效应细胞在体内检测不到后,再给予在后疗程的免疫效应细胞;或者在所述在先疗程给予后约4周至24周的时间点处给予所述的在后疗程的免疫效应细胞。
- 如权利要求4所述的方法,其特征在于,在后疗程给予的免疫效应细胞的剂量低于、等于、或高于在先疗程给予的免疫效应细胞,优选地,在后疗程给予的免疫效应细胞的剂量高于在先疗程给予的免疫效应细胞,更优选地,所述在后疗程给予的免疫效应细胞的剂量是在先给予的免疫效应细胞的剂量的2倍、5倍、7倍或10倍。
- 如权利要求4所述的方法,其特征在于,给予在后疗程的免疫效应细胞时,所述受试者具有以下任一特征:(i)指示细胞因子释放综合征(CRS)的因子在受试者中血清水平倍数比在给予在先疗程的免疫效应细胞之前即刻的受试者中的水平小约10倍、小约25倍、和/或小约50倍;(ii)没有显示出3级或更高的神经毒性;(iii)神经毒性或CRS水平与给予在先疗程的免疫效应细胞后的神经毒性或CRS水平的峰值水平相比,呈现降低;或者(iv)所述受试者没有显示出针对由在先疗程的细胞表达的CAR的可检测的体液或细胞介导的免疫应答。
- 如权利要求7所述的方法,其特征在于,所述(iii)中,CRS水平与给予在先疗程的免疫效应细胞后的CRS的峰值水平相比,降低至少50%,优选的,降低至少20%,更优的,降低至少5%,或者CRS水平与给予在先疗程的免疫效应细胞之前的CRS水平相当。
- 如权利要求1所述的方法,其特征在于,所述方法还包括在给予所述的免疫效应细胞的之前进行预处理,所述预处理包括给予所述受试者化疗剂或者辐射治疗,或其组合,优选所述预处理在给予免疫效应细胞前2-12天实施,进一步优选,在给予免疫效应细胞前2-7天实施预处理。
- 如权利要求9所述的方法,其特征在于,所述化疗剂包含以下任意一种或其组合:环磷酰胺、氟达拉滨。
- 如权利要求10所述的方法,其特征在于,当使用氟达拉滨时,所述氟达拉滨的给予量约为10-50mg/m 2/天、或约15-40mg/m 2/天、或约15-35mg/m 2/天、或 15-30mg/m 2/天、或约20-30mg/m 2/天;优选的,所述氟达拉滨的给予量约为20-30mg/m 2/天;优选的,所述氟达拉滨的给予量约为20-26mg/m 2/天;当使用环磷酰胺时,所述环磷酰胺的给予量约为100-700mg/m 2/天、或约150-600mg/m 2/天、或约190-600mg/m 2/天、或约190-560mg/m 2/天;优选的,所述环磷酰胺的给予量约为150-400mg/m 2/天,优选的,约为190-350mg/m 2/天;优选的,所述环磷酰胺的给予量约为400-600mg/m 2/天,优选的,约为450-600mg/m 2/天,更优选的,约为450-560mg/m 2/天。
- 如权利要求10所述的方法,其特征在于,所述化疗剂连续使用不超过6天;当使用氟达拉滨时,优选所述环磷酰胺连续使用1-5天,当使用氟达拉滨时,优选所述氟达拉滨连续使用2-4天。
- 如权利要求1所述的方法,其特征在于,所述肿瘤为多发性骨髓瘤。
- 如权利要求1所述的方法,其特征在于,所述嵌合抗原受体包括特异性结合BCMA的抗体、跨膜域及胞内域,所述抗体的重链可变区和轻链可变区具有:SEQ ID NO:1所示的HCDR1、SEQ ID NO:2所示的HCDR2、SEQ ID NO:3所示的HCDR3,以及SEQ ID NO:6所示的LCDR1、SEQ ID NO:7所示的LCDR2、SEQ ID NO:8所示的LCDR3;或者SEQ ID NO:1所示的HCDR1、SEQ ID NO:2所示的HCDR2、SEQ ID NO:4所示的HCDR3,以及SEQ ID NO:6所示的LCDR1、SEQ ID NO:7所示的LCDR2、SEQ ID NO:9所示的LCDR3;或者SEQ ID NO:1所示的HCDR1、SEQ ID NO:2所示的HCDR2、SEQ ID NO:5所示的HCDR3以及SEQ ID NO:6所示的LCDR1、SEQ ID NO:7所示的LCDR2、SEQ ID NO:10所示的LCDR3;或者SEQ ID NO:11所示的HCDR1、SEQ ID NO:12所示的HCDR2、SEQ ID NO:5所示的HCDR3,以及SEQ ID NO:6所示的LCDR1、SEQ ID NO:7所示的LCDR2、SEQ ID NO:10所示的LCDR3;或者SEQ ID NO:13所示的HCDR1、SEQ ID NO:14所示的HCDR2、SEQ ID NO:5所示的HCDR3,以及SEQ ID NO:6所示的LCDR1、SEQ ID NO:7所示的LCDR2、SEQ ID NO:10所示的LCDR3。
- 如权利要求1所述的方法,其特征在于,所述的所述嵌合抗原受体包括特异性结合BCMA的抗体、跨膜域及胞内域,所述抗体的轻链可变区具有SEQ ID NO:6所示的LCDR1、SEQ ID NO:7所示的LCDR2、SEQ ID NO:10所示的LCDR3。
- 如权利要求15所述的方法,其特征在于,所述抗体的轻链可变区具有SEQ ID NO:20所示的氨基酸序列;或者所述抗体的重链可变区具有SEQ ID NO:5所示的HCDR3。
- 如权利要求14所述的方法,其特征在于:所述的抗体的重链可变区具有SEQ ID NO:15所示的氨基酸序列并且所述抗体的轻链可变区具有SEQ ID NO:16所示的氨基酸序列;或者所述的抗体的重链可变区具有SEQ ID NO:17所示的氨基酸序列并且所述抗体的轻链可变区具有SEQ ID NO:18所示的氨基酸序列;或者所述的抗体的重链可变区具有SEQ ID NO:19所示的氨基酸序列并且所述抗体的轻链可变区具有SEQ ID NO:20所示的氨基酸序列;或者所述的抗体的重链可变区具有SEQ ID NO:21所示的氨基酸序列并且所述抗体的轻链可变区具有SEQ ID NO:20所示的氨基酸序列;或者所述的抗体的重链可变区具有SEQ ID NO:23所示的氨基酸序列并且所述抗体的轻链可变区具有SEQ ID NO:20所示的氨基酸序列。
- 如权利要求17所述的方法,其特征在于,所述抗体具有SEQ ID NO:25、27、或29所示的scFv的序列。
- 如权利要求14所述的方法,其特征在于,所述的嵌合抗原受体具有SEQ ID NO:30、31、32、33、34、35、36、37、38、39、40、或41所示氨基酸序列;优选地,所述的嵌合抗原受体具有SEQ ID NO:36、37、38任一所示的氨基 酸序列;更优选地,所述的嵌合抗原受体具有SEQ ID NO:36所示的氨基酸序列。
- 如权利要求1-19中任一项所述的方法,其特征在于,所述免疫效应细胞是T细胞、NK细胞或者NKT细胞;优选地,所述免疫效应细胞是T细胞,进一步优选,所述免疫效应细胞来自所述受试者自体。
- 如权利要求1所述的方法,其特征在于,每个疗程的免疫效应细胞的给药间隔是约4周至24周;优选的,每个疗程的免疫细胞数量基本相同;优选的,在后疗程给予的免疫效应细胞的数量高于在先给的在后疗程的免疫细胞数;优选的,在后疗程给予的免疫效应细胞数量低于在先给的在后疗程的免疫细胞数。
- 如权利要求1所述的方法,其特征在于,给予所述免疫效应细胞之前,所述受试者没有接受过靶向BCMA的表达嵌合抗原受体的免疫细胞的治疗;或者在给予所述免疫效应细胞治疗之前,所述受试者已经进行了手术治疗、化疗、或者不同于权利要求1所述的免疫治疗。
- 如权利要求1所述的方法,其特征在于,在给予每个疗程的免疫效应细胞之前,对所述受试者的指示CRS的因子、指示神经毒性的因子、指示肿瘤负荷的因子、和/或指示宿主抗-CAR免疫应答的因子的血清水平进行评价;其中,所述的指示肿瘤负荷的因子为:所述受试者的肿瘤细胞总数、或者所述受试者的器官中肿瘤细胞总数、或者所述受试者的组织中的肿瘤细胞总数、或者肿瘤的质量或体积,或者肿瘤转移的程度、或者肿瘤数量。
- 如权利要求23所述的方法,其特征在于,包括:i)在给予在后疗程之前评价指示肿瘤负荷的因子;和ii)基于所述评价的结果,确定在后疗程,并且iii)如果评价确定所述受试者的肿瘤质量或体积稳定或下降,给予所述受试者包含少于或多于所述在先疗程中的CAR表达细胞的数量或与其大约相同的CAR表达细胞的数量的在后疗程。
- 如权利要求1所述的方法,其特征在于,所述免疫效应细胞的给药剂量为约0.1x10 6细胞/kg受试者体重~5x10 7细胞/kg,或者所述免疫效应细胞的给药总剂量为约0.1x10 7细胞~1x10 10细胞;优选的,为约0.5x10 6细胞/kg~1x10 7细胞/kg,或者所述免疫效应细胞的给药总剂量为约0.1x10 8细胞~1x10 9细胞;更优选的,为约0.9x10 6细胞/kg~5x10 6细胞/kg,或者所述免疫效应细胞的给药总剂量为约0.1x10 8细胞~9x10 8细胞。
- 如权利要求1所述的方法,其特征在于,所述受试者的BCMA的表达阳性率大于50%,优选的,大于70%,或者大于80%;更优选的,大于85%;更优选的,大于90%。
- 如权利要求1所述的方法,其特征在于,所述受试者的疾病分型为IgGκ型、或者IgGλ型、或者IgAλ型、或者IgAκ型、或者λ轻链型。
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AU2019310855A1 (en) | 2021-03-11 |
EP3834849A1 (en) | 2021-06-16 |
CA3107515A1 (en) | 2020-01-30 |
AU2019310855A2 (en) | 2021-03-18 |
CN112930199A (zh) | 2021-06-08 |
US20210292427A1 (en) | 2021-09-23 |
EP3834849A4 (en) | 2022-08-03 |
JP2021535082A (ja) | 2021-12-16 |
KR20210055034A (ko) | 2021-05-14 |
JP7262568B2 (ja) | 2023-04-21 |
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